CliniCal praCtiCe guideline for the prevention of venous thromboembolism

Transcription

Clinical practice guideline
for the prevention of venous thromboembolism
(deep vein thrombosis and pulmonary embolism)
in patients admitted to Australian hospitals
DRAFT FOR
PUBLIC CONSULTATION
2009
© Commonwealth of Australia 2009
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This work is copyright. You may download, display, print and reproduce this material in unaltered form
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Attorney-General’s Department, Robert Garran Offices, National Circuit, Canberra ACT 2600 or posted at:
http://www.ag.gov.au/cca
Draft for Public Consultation
national health and medical research council
Table of contents
Executive Summary
v
1 Introduction
1
1.1 Background
1.2 Clinical need for this Guideline
1.3 Purpose of this Guideline
1.4 Intended users
1.5 Scope of this Guideline
1.6Methods used to develop this Guideline
1.7 Scheduled review of this Guideline
1.8 Funding
1
1
2
2
2
3
4
4
2 Options for thromboprophylaxis in Australia
5
3 Issues to be considered in using this Guideline
7
3.1 Diagnosis of VTE
3.2Endpoints for VTE prevention
3.3 Applicability of evidence – issues to consider
3.4 Balancing risks
7
7
7
8
4 Patient risk
9
4.1 VTE risk
4.2 Bleeding risk
4.3 VTE risk assessment
5 Summary of recommendations
9
10
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11
5.1 Surgical patients
5.2 Anaesthesia
5.3Medical patients
5.4 Cancer patients
5.5 Pregnancy and childbirth
6Evidence and recommendations
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6.1 Surgical patients – Evidence and recommendations for VTE prophylaxis
6.1.1 Total hip replacement
6.1.2Hip fracture surgery
6.1.3 Total knee replacement
6.1.4 Knee arthroscopy
6.1.5 Lower leg fractures and injuries with immobilisation
6.1.6 General surgery
6.1.7 Urological surgery
6.1.8 Gynaecological surgery
6.1.9 Abdominal surgery
6.1.10 Cardiac, thoracic and vascular surgery
6.1.11 Neurosurgery
6.1.12 Trauma surgery or spinal surgery
Clinical practice guideline for the prevention of venous thromboembolism in patients admitted to Australian hospitals |
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6Evidence and recommendations (continued)
6.2 Anaesthesia
6.3Medical patients – Evidence and recommendations for VTE prophylaxis
6.3.1 Stroke
6.3.2Myocardial infarction (MI)
6.3.3 General medical
6.4 Cancer patients – Evidence and recommendations for VTE prophylaxis
6.5 Pregnancy and childbirth – Evidence and recommendations for VTE prophylaxis
7 Areas for future research
7.1 Risk of VTE
7.2Effectiveness of thromboprophylactic agents
7.3 Areas with little evidence for effective thromboprophylaxis
7.4 Other issues
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8 References
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9 Appendices
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Appendix A: VTE Prevention Guideline Adaptation Committee
A.1:Membership of the VTE Prevention Guideline Adaptation Committee
A.2: Declarations of Interest of the VTE Prevention Guideline Adaptation Committee
A.3: Terms of Reference of the VTE Prevention Guideline Adaptation Committee
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Appendix B: Overview of the guideline development process
B.1: Appointing the Committee
B.2 Declaration of interest process
B.3: Steps in the development of an NHMRC clinical practice guideline
B.3i Developing structured clinical questions
B.3ii Selecting high quality source guidelines to use for adaptation
B.3iii Developing a search strategy and searching the literature
B.3iv Assessing the eligibility of studies
B.3v Inclusion criteria
B.3vi Critically appraising included studies
B.3vii Summarise and where appropriate statistically pool the relevant data
B.3viii Assess the body of evidence and formulate recommendations
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Appendix C:Clinical questions
Appendix D:Evidence tables
Appendix E: NHMRC Evidence Statement Form
Appendix F: Abbreviations and glossary of terms
Appendix G:Acknowledgements
Disclaimer
This document is a general guide to appropriate practice, to be followed subject to the clinician’s judgment and patient’s
preference in each individual case. The guideline is designed to provide information to assist decision-making and is based
on the best evidence available at the time of development of this publication .
iv | Clinical practice guideline for the prevention of venous thromboembolism in patients admitted to Australian hospitals
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Executive summary
Although effective pharmacological and mechanical preventive options have existed for decades,
venous thromboembolism (VTE) remains a major cause of morbidity and a significant cause of
mortality in hospitalised patients across Australia and internationally. Data from research and
clinical audits suggest that the available preventive options are under-utilised and inconsistently
applied. Variations in practice and the emergence of new anticoagulants underline the need
for an evidence-based VTE prevention guideline suited to the Australian healthcare context.
This Guideline provides recommendations on thromboprophylaxis for adult patients admitted
to Australian hospitals. It covers patients undergoing all major types of surgery, patients with
acute medical illnesses, trauma patients, patients admitted to intensive care units, cancer patients,
and patients hospitalised during pregnancy and the puerperium.
The Guideline was prepared largely through critical appraisal and adaptation of existing
high-quality international VTE prevention guidelines, in preference to a re-examination of
primary research publications and systematic reviews. From the critical appraisal, the main source
of evidence selected was a guideline produced in 2007 by the National Institute for Health
and Clinical Excellence (NICE) in the UK. The adaptation of existing guidelines expedited
the development of this Guideline, a consultation draft of which was produced within
approximately 12 months.
A multidisciplinary VTE Prevention Guideline Adaptation Committee, comprising experts in the
prevention of VTE and a consumer representative, was appointed by the NHMRC to provide
advice on the following: the questions that directed the search for evidence; the selection of
guidelines for adaptation; the adaptation process; the interpretation of primary research findings
where existing guidelines did not provide sufficient evidence; and the framing of the clinical
practice recommendations.
In assessing the evidence from the existing guidelines and other sources, the Committee took
account of potential biases in clinical trials. These biases resulted from the different methods
used for the diagnosis of VTE and the different endpoints taken as reflecting the occurrence
of VTE. The Committee also examined the applicability of the evidence to current Australian
hospital practice.
In framing the Guideline recommendations, the Committee placed great emphasis on
balancing the risks of VTE in hospitalised patients against the actual and perceived risks of
pharmacological thromboprophylaxis and patients’ tolerance of pharmacological (especially
injectable) and mechanical prophylaxis. Bleeding is the major complication of pharmacological
thromboprophylaxis, and is a potential side-effect of all anticoagulants. The risks of both VTE
and bleeding vary with individual patient factors, the presence of acute medical illnesses, types
of surgical procedures, and duration and nature of immobilisation. The consequences of bleeding
also vary with different surgical procedures and different anatomical sites.
The pharmacological options considered in the Guideline are unfractionated heparin, low
molecular weight heparin, fondaparinux, danaparoid (a heparinoid), rivaroxaban, dabigatran
etexilate, aspirin and warfarin. The mechanical options are graduated compression stockings,
intermittent pneumatic compression devices and foot pumps.
The Guideline contains 64 recommendations. Each recommendation is assigned a grade from
‘A’ to ‘D’. ‘A’ refers to a recommendation based on a body of evidence that can be trusted to
guide practice. ‘B’ refers to a recommendation based on a body of evidence that can be trusted
to guide practice in most situations. Grade ‘C’ means that the body of evidence provides some
support for the recommendation, but care should be taken in its application. Grade ‘D’ means
v
that the body of evidence is weak and the recommendation should be applied with caution.
Where no good-quality evidence was available but there was consensus among Committee
members, consensus-based recommendations are given. Such recommendations are called
Good Practice Points. Within the Guideline, recommendations are presented by clinical
procedure (e.g. total hip replacement, hip fracture surgery, general surgery, gynaecological
surgery) and medical condition (e.g. stroke, myocardial infarction). Specific sections are included
for cancer patients surgical and non-surgical) and pregnancy and childbirth. A summary of
all the recommendations is provided in section 5. The evidence for each recommendation is
presented by clinical procedure and set out in a summary within section 6. Finally, the Guideline
sets out a short list of areas for future research.
The recommendations are intended to encapsulate the available evidence on the prevention
of VTE. However, they should only be followed subject to the judgement of clinicians caring
for individual patients and patients’ own preferences.
vi | Clinical practice guideline for the prevention of venous thromboembolism in patients admitted to Australian hospitals
1 Introduction
1.1 Background
Deep vein thrombosis (DVT) and pulmonary embolism (PE) are two aspects of one disease process
known as venous thromboembolism (VTE). In DVT, a thrombus (blood clot) forms in the deep
veins of the leg or pelvis where it may cause pain, tenderness and swelling of the leg. In PE,
some or all of the thrombus becomes detached and moves from the vein through the right side of
the heart to lodge in one or more pulmonary arteries. PE may cause shortness of breath, bloody
sputum, chest pain, faintness and heart failure. Massive PE leads to death.
Hospitalised patients are over 100 times more likely to develop a DVT or PE compared with the
rest of the community.1 Each year approximately 30,000 people are hospitalised in Australia as a
consequence of VTE, and an estimated 2,000 die from VTE.2 The majority of VTE cases requiring
hospitalisation are related to previous hospital admission for surgery or acute illness. Many of these
cases are preventable.2 PE is one of the commonest causes of death in hospital, accounting for
10 percent of all hospital deaths.3 Other significant long-term morbidity, costs and consequences
are also associated with the occurrence of VTE.3
The options for thromboprophylaxis comprise pharmacological agents (anticoagulants) and
mechanical methods, alone or in combination. The most commonly-used pharmacological agents
in Australia are the heparins (low molecular weight heparin and unfractionated heparin sodium).
Other agents include fondaparinux, danaparoid, warfarin and aspirin. The direct thrombin inhibitor
dabigatran etexilate and the selective direct factor Xa inhibitor rivaroxaban were approved by
the Therapeutic Goods Administration (TGA) for limited indications in late 2008. Mechanical
prophylaxis options include thigh or knee length graduated compression stockings, pneumatic
venous pumping devices that intermittently compress the calf muscles and devices that stimulate
lower-limb muscle contraction. All the thromboprophylactic options that were considered for
inclusion in this Guideline are described in section 2.
1.2 Clinical need for this Guideline
A strong evidence base exists for VTE prevention, and VTE prevention in hospitalised patients
has been widely acknowledged in Australia and internationally as a major opportunity to improve
patient safety.4,5 Although several Australian and international VTE prevention guidelines have been
published in recent years,6-12 no guidelines for the prevention of VTE have been endorsed by the
National Health and Medical Research Council (NHMRC).
Effective VTE prevention measures have been widely reported to be under-utilised and
inconsistently applied.13,14 For example, a recent UK survey reported that 71 percent of hospitalised
patients judged to be at moderate or high risk of DVT did not receive any form of prophylaxis.15
VTE leads to short and long term morbidity and mortality and is costly to treat. In addition to
diagnostic tests, patients with VTE require treatment with anticoagulants and a longer hospital stay.
They often require further diagnostic tests and prolonged treatment to manage the complications of
VTE post-discharge.16
An evidence-based prevention guideline that sets out clear nationally-agreed recommendations
suitable for the Australian clinical context will help to reduce the incidence of VTE, the occurrence
of chronic sequelae, and subsequent costs associated with managing VTE.
1
1.3 Purpose of this Guideline
The purpose of this Guideline is to provide practical, evidence-based recommendations for
the prevention of VTE in adult surgical and medical patients and pregnant women admitted to
Australian metropolitan, regional and rural hospitals. The recommendations should be followed
subject to the judgement of clinicians caring for individual patients and patients’ own preferences.
1.4 Intended users
This Guideline is intended for doctors, nurses, pharmacists and allied health professionals. It also
provides useful information for consumers and those responsible for the quality and safety of
health care.
1.5 Scope of this Guideline
This Guideline provides recommendations on thromboprophylaxis for adult patients admitted
to Australian hospitals in the following categories:
•patients undergoing surgery including orthopaedic, major general, major gynaecological,
urological, cardiothoracic, vascular and neurosurgery
•patients with acute medical illnesses, including myocardial infarction, stroke, and other
medical conditions
•trauma patients
•patients admitted to intensive care units
•cancer patients (active or occult, with or without cancer treatment)
•patients admitted during pregnancy and the puerperium.
This Guideline does not provide recommendations on thromboprophylaxis for:
•patients under the age of 18 years
•patients attending hospital as outpatients
•patients who present to emergency departments but are not admitted
•elderly or immobile patients cared for at home or in external residential accommodation
(unless admitted to hospital)
•patients in long-term hospital rehabilitation
•patients who have not been hospitalised
•travel-related VTE.
2 | Clinical practice guideline for the prevention of venous thromboembolism in patients admitted to Australian hospitals
1.6Methods used to develop this Guideline
The National Institute of Clinical Studies (NICS), an institute of the NHMRC, developed this
Guideline in accordance with NHMRC guideline development processes.17-19
In July 2008, NICS convened a multidisciplinary committee comprising professional group
members with specific expertise in VTE prevention and a consumer representative. Details of the
membership of the VTE Prevention Guideline Adaptation Committee (the Committee) are provided
in Appendix A.1 and the process for their appointment can be found in Appendix B.1. The terms
of reference for the Committee are provided in Appendix A.3.
As a number of high quality international VTE prevention guidelines were already available, NICS
developed this Guideline using an established guideline adaptation methodology (ADAPTE) rather
than developing a new guideline de novo.20 ADAPTE seeks to reduce duplication in guideline
development by using existing high-quality guidelines as the basis for a local guideline.
Following the ADAPTE process, the Committee considered that the 2007 publication from the
UK’s National Institute for Health and Clinical Excellence (NICE)8 best met the criteria for a high
quality source guideline. This guideline was selected using the Appraisal of Guidelines Research
and Evaluation instrument (AGREE),21 which measures the extent to which the potential biases
of guideline development have been adequately addressed, internal and external validity of the
recommendations, and feasibility for practice, but does not assess the content of the guideline.
Although the 2007 NICE VTE prevention guideline was considered the most comprehensive review
of available evidence, its structure was unsuitable for direct adaptation into an Australian guideline.
The NICE guideline grouped all surgical procedures together, and the Committee considered that
this would not be clinically meaningful in the Australian context. The Committee also considered
that the evidence for individual surgical procedures needed to be examined separately, as the
patient risk profile for each procedure differed and overall recommendations for practice were not
expected to be clinically relevant to practitioners from different surgical and medical specialties.
The Committee consulted the American College of Chest Physicians (ACCP) VTE Prevention Guideline
to assist in framing the clinical questions as its structure was regarded more clinically useful.7
As the adaptation process progressed, the Committee found that evidence and recommendations
could not be taken from existing guidelines (i.e. the ADAPTE process could not be followed entirely).
Therefore, the Committee resolved to use a modified guideline adaptation process based in principle
on ADAPTE but incorporating elements of de novo guideline development. Consequently, the
evidence in the NICE guideline was re-ordered and re-analysed to match the desired structure of this
NHMRC Guideline and the Committee formulated recommendations based on these new analyses.
The Guideline recommendations were developed using procedures outlined in the “NHMRC
additional levels of evidence and grades for recommendations for developers of guidelines:
Stage 2 consultation 2008-2010”.22 Each recommendation was assigned a grade by the Committee,
taking into account the volume, consistency, generalisability, applicability and clinical impact of
the body of evidence supporting each recommendation. The table in Appendix B.3viii sets out
the evidence gradings.22 A standardised evidence statement form used to formulate and grade
the recommendations can be found in Appendix E.22 Good practice points were used when the
conventional grading of evidence was not possible. These points represent consensus views of the
VTE Prevention Guideline Adaptation Committee and are identified throughout by the abbreviation
GPP (in place of a recommendation grading).
A detailed report on the modified ADAPTE process used to develop this Guideline is provided
in Appendix B.
3
1.7 Scheduled review of this Guideline
NHMRC recommends that guidelines be reviewed and revised no more than five years after initial
publication. However, the evidence base on which this Guideline was developed is likely to
change sooner. Therefore, the Committee will be re-convened to review relevant sections of this
Guideline if any of the following occur within five years:
•registration by the Australian Therapeutic Goods Administration of any new drugs for the
prevention of VTE in hospitalised patients
•a change in the indications registered by the Australian Therapeutic Goods Administration for
any drug included in this Guideline
•publication of any new major randomised controlled trials or systematic reviews that potentially
have a bearing on the recommendations in this Guideline
•emergence of any major safety concerns relevant to this Guideline.
1.8 Funding
The development of this Guideline was funded by the National Health and Medical Research
Council (NHMRC).
2 Options for thromboprophylaxis in Australia
Adequate hydration and early mobilisation are simple measures that should be applied as standard
practice to prevent VTE. Other important options for VTE prophylaxis include pharmacological
or mechanical methods. Their effectiveness varies depending upon the clinical procedure and
patient-related risk factors.
The pharmacological options considered for this Guideline were:
•subcutaneously administered unfractionated heparin (UFH) or low molecular weight
heparins (LMWH)
•subcutaneously administered pentasaccharide fondaparinux which is a selective
inhibitor of activated Factor X (Xa)
•subcutaneously administered heparinoid, danaparoid
•orally administered direct factor Xa inhibitor, rivaroxaban
•orally administered direct thrombin inhibitor, dabigatran etexilate
•orally administered aspirin
•orally administered vitamin K antagonist, warfarin.
Low molecular weight heparin, unfractionated heparin, fondaparinux, danaparoid, rivaroxaban,
dabigatran etexilate, aspirin and warfarin were treated as separate classes of agents for the
purposes of the review of evidence for this Guideline.
Immobility can lead to the development of DVT as normal venous pump function of skeletal
muscles is greatly reduced. Patients may be immobilised through confinement to bed, as a
consequence of a surgical procedure, because of local immobilisation (e.g. a plaster cast or
traction applied to a limb), or a combination of these. Mechanical methods of prophylaxis focus
on reducing venous stasis and blood stagnation by promoting venous blood flow through external
compression (with graduated compression stockings, intermittent pneumatic compression or
venous foot pumps, used alone or in combination).
The mechanical options considered for this Guideline were:
•knee or thigh length graduated compression stockings (GCS)
•knee or thigh length intermittent pneumatic compression (IPC)
•venous foot pumps including foot impulse technology (FIT) and foot impulse devices (FID).
For further information on indications, contraindications and precautions relating to the
agents used for preventing VTE, refer to the Australian Medicines Handbook,23 or individual
manufacturer’s instructions.
5
3 Issues to be considered in using this Guideline
3.1 Diagnosis of VTE
A clinical diagnosis of DVT is usually confirmed by compression ultrasonography. Some of the
randomised controlled trials that formed the evidence base for this Guideline relied on compression
ultrasound as the primary method of detecting or excluding a DVT in both the intervention and
control groups as ultrasound is non-invasive. Most trials used ascending venography, considered to be
the ‘gold standard’ diagnostic tool. Venography has a greater sensitivity than compression ultrasound
for distal (below-knee) DVT, but is an invasive technique and rarely used in clinical practice.
PE is usually diagnosed or excluded by computed tomographic (CT) pulmonary angiography
(helical CT) or ventilation-perfusion isotope scan. Routine screening for PE was not usually
performed in the randomised controlled trials reviewed in this Guideline. Instead, trial subjects
were assessed only on clinical suspicion of PE, based on symptoms, signs and other investigations.
Therefore, the actual incidence of PE may have been underestimated.
When reviewing evidence, the Committee discounted diagnostic methods that are incompletely
validated (e.g. Magnetic Resonance Imaging for DVT) or have limited accuracy for sub-clinical DVT
(e.g. impedance plethysmography).
3.2Endpoints for VTE prevention
The Committee accepted evidence on the efficacy of prophylaxis derived using objectively
documented outcome measures across the full spectrum of VTE, including asymptomatic, distal
or proximal DVT detected by venography or ultrasound imaging, as well as symptomatic and
confirmed DVT or PE (non-fatal or fatal).
The Committee acknowledges the continuing debate on the clinical relevance of asymptomatic
distal DVT as an indicator of the efficacy of VTE prophylaxis. Some experts have argued that
guideline committees should consider evidence only on symptomatic VTE or only symptomatic PE.
This Committee’s decision to consider outcomes across the broad spectrum was based on the fact
that VTE is a spectrum of disease, from asymptomatic distal DVT to PE, and most DVTs (and PE)
are initially asymptomatic.
3.3 Applicability of evidence – Issues to consider
The Committee recognised a number of issues concerning the applicability of the evidence to
current practice in Australia.
Early comparisons of active VTE prevention (usually using unfractionated or low molecular
weight heparin) with a placebo or no intervention were undertaken decades ago, when surgical
techniques, anaesthesia and postoperative management were very different. Importantly, the
emphasis on early postoperative mobilisation was not as strong as it is today. The results of early
studies of VTE prevention may therefore not always apply to contemporary practice. It seems
likely that contemporary clinical management may have led to reductions in the risk of VTE, even
in the absence of specific prophylactic measures. Nevertheless, VTE remains a major complication
of hospitalisation and the existing guidelines are a response to that risk.
Therapeutic regimens in clinical trials may differ from those in current practice. For example, a
preoperative low molecular weight heparin dose is required by many VTE prevention trials in
orthopaedic surgery but is almost never administered in current practice in Australia.
7
The risk of bleeding related to surgery is the main complication of pharmacological prophylaxis.
‘Major bleeding’, as variously defined in clinical trials, bears a limited relation to ‘major bleeding’
as perceived by surgeons or patients. Differing perceptions of risk for ‘major bleeding’ strongly
determine surgeons’ attitudes to various forms of prophylaxis – even though recorded likelihood
of ‘major bleeding’ has been small in clinical trials.
These perceptions may also influence the choice between pharmacological and mechanical forms
of VTE prophylaxis that enhance venous return and/or prevent venous stasis (e.g. with various
intermittent pneumatic compression devices).
Finally, there are far fewer studies of mechanical than pharmacological prophylaxis, and fewer
studies where one was followed by the other. A lack of available evidence in important areas
necessarily limits the scope of evidence-based recommendations.
3.4 Balancing risks
The risk of VTE in hospitalised patients must be balanced against the actual and perceived risks
of pharmacological thromboprophylaxis and patients’ tolerance of pharmacological (especially
injectable) or mechanical prophylaxis. Evidence presented throughout this Guideline shows that
the risk of major bleeding associated with anticoagulant agents is low.
With major orthopaedic surgery, reported 30-day rates of major bleeding in patients receiving
heparins were 0.2-1.7 percent; similar to placebo rates in the same trials of 0.2-1.5 percent.24,25
However, clinicians’ and patients’ perceive the bleeding risk as significant. In particular, surgeons
may be understandably reluctant to expose patients to the risk of excessive intra- or postoperative
bleeding and the subsequent complications, especially in procedures such as joint replacement
where bleeding can lead to severe infections and a need to explant prostheses.
This Guideline is intended to assist clinicians in balancing the risks of death and serious morbidity
from VTE against the complications and disadvantages of prophylaxis.
4 Patient risk
4.1 VTE risk
The likelihood of developing a VTE is increased by well-recognised risk factors. However, there are
few population-based studies on VTE risk in hospitalised patients, and estimates of the magnitude
of risk are sometimes contradictory or outdated (for example, by changes in surgical techniques or
patient characteristics).
There are no evidence-based algorithms for assigning a patient to ‘low’ or ‘high’ risk categories,
based on single risk factors or combinations of risk factors. Known risk factors are listed below,
and their presence or absence should inform clinical decisions on the use of thromboprophylaxis.
The risk factors are grouped into the following categories: individual patient risk factors; risks
related to an acute medical illness; and risks related to an injury or a surgical procedure. Risks
related to the individual may be either inherited or exogenous. Depending on their magnitude
the risk factors related to an injury, a surgical procedure, or an acute medical illness often exert
a dominating influence for their duration.
1. Individual patient risk factors:
• age (the annual incidence of VTE rises with each decade over the age of forty)26-28
• pregnancy and the puerperium29
• active or occult malignancy27,28,30-32
• previous VTE27,32
• varicose veins32
• marked obesity32-34
• prolonged severe immobility (prolonged bed rest, immobilisation in a plaster cast or
brace or prolonged travel resulting in limited movement and subsequent venous stasis)30,35
• use of oestrogen-containing hormone replacement therapy or oral contraceptives
in women32,33,36
• inherited or acquired thrombophilia (conditions that carry a high risk of VTE include
inherited deficiency of antithrombin, protein C or protein S, homozygosity or double
heterozygosity for factor V Leiden or the G20120A prothrombin gene mutation, the
phospholipid antibody syndrome).33
2. Risks related to an acute medical illness:
• acute or acute on chronic chest infection32
• heart failure30,32
• myocardial infarction32
• stroke with immobility37
• some forms of cancer chemotherapy28,30
• acute inflammatory bowel disease.32
3. Risks related to an injury or surgical procedure:
• all surgical procedures but especially abdominal,38 pelvic,8 thoracic or orthopaedic surgical
procedures39-42
–– risk is determined by the type of surgery (major joint surgery carries a very high risk,39-42
as does curative surgery for cancer43), the type of anaesthesia,44 the likely duration of
immobility (including duration of surgery),30,35 and surgical complications
• leg injury that requires surgery or prolonged immobilisation.45
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4.2 Bleeding risk
The risk of bleeding is elevated in the presence of certain risk factors and when certain procedures
are undertaken. Pharmacological thromboprophylaxis may add to these risks.
Patient-related risk factors for bleeding include abnormal blood coagulation or low platelet count.
Pharmacological VTE prophylaxis may also be contraindicated in patients with the following
characteristics:
•recent central nervous system bleeding
•intracranial or spinal lesion at high risk for bleeding
•current active major bleeding, defined as requiring at least two units of blood or blood products
to be transfused in 24 hours
•current chronic, clinically significant and measurable bleeding over 48 hours
•thrombocytopenia (platelets < 50,000/μl)
•severe platelet dysfunction
•recent major surgical procedure at high risk for bleeding
•underlying coagulopathy or coagulation factor abnormalities
•regional axial anaesthesia or recent lumbar puncture for any reason
•high risk of falls.
By nature of its mechanism of action, pharmacological prophylaxis may increase the risk of surgical
bleeding. With pharmacological prophylaxis, bleeding risk can be related to dose and treatment
schedule (especially the timing of prophylaxis relative to surgery). An assessment of bleeding risk
is an essential step in deciding on appropriate prophylaxis for individual patients.
4.3 VTE risk assessment
It is essential to perform and record a VTE risk assessment in each patient before deciding whether
or not to use preventive measures and on the most appropriate measures to use.
VTE risk factors are thought to be additive so the presence of multiple risk factors leads to a
higher risk of developing VTE. The presence of multiple risk factors may signal the need for more
efficacious VTE prophylactic regimens.
A VTE risk assessment should follow the following steps:
Step 1
Assess the patient’s baseline risk of VTE, taking into account inherited and acquired risk factors such as those listed in section 4.1.
Step 2
Assess the patient’s additional risk of VTE, taking account of the reasons for hospitalisation (surgical procedures, trauma or specific medical illness).
Step 3
Assess the patient’s risk of bleeding.
Step 4
Formulate an overall risk assessment (with consideration of VTE risk and bleeding risk).
Step 5
Select appropriate methods of thromboprophylaxis based on the risk assessment.
5 Summary of recommendations
This summary section provides a list of the evidence-based recommendations detailed in the
text of section 6. Each of the recommendations is given an overall grading based on the NHMRC
additional levels of evidence and grades of recommendation (2008-2010). When no Level I or II
evidence was available but there was consensus among the committee, recommended best practice
points have been provided, and can be identified throughout the guideline with the following:
Good practice point (GPP)
Consensus recommendations and recommendations for further research have not been graded.
Grade of
recommendation
Description
A
Body of evidence can be trusted to guide practice
B
Body of evidence can be trusted to guide practice in most situations
C
Body of evidence provides some support for recommendation(s) but care should be taken in
its application
D
Body of evidence is weak and recommendation must be applied with caution
NA
Not applicable – unable to grade body of evidence
GPP
Good practice point – consensus-based recommendations
Interpreting guideline recommendations
Where the words “use” or “recommended” are used in this Guideline, the Committee judged
that the benefits of the recommended approach clearly exceed the harms, and that the evidence
supporting the recommendation was trusted to guide practice.
Where the words “should be considered” are used, either the quality of evidence was
underpowered, or the available studies demonstrated little clear advantage of one approach over
another or the balance of benefits to harm was unclear.
Where the words “not recommended” are used, there is either a lack of appropriate evidence, or
the harms outweigh the benefits.
The full evidence tables supporting the recommendations can be found in Appendix D and
for details on contraindications to thromboprophylaxis refer to the 2009 Australian Medicines
Handbook.23
The following tables provide a summary of the recommendations for the prevention of VTE by
clinical procedure. For further information on the evidence from which these recommendations are
based, as well as dose, duration, timing and precautions, please refer to section 6.
11
5 Summary of recommendations (cont.)
5.1 Surgical patients
Grade
Evidence
in section
1. Use thromboprophylaxis for all patients admitted to hospital for total hip replacement.
GPP
6.1.1
2. In the absence of contraindications, commence pharmacological thromboprophylaxis
postoperatively and continue for up to 35 days following total hip replacement surgery.
Use one of the following:
• low molecular weight heparin
• fondaparinux
• rivaroxaban
• dabigatran etexilate.
A
B
B
B
6.1.1
6.1.1
6.1.1
6.1.1
3. Preoperative administration of thromboprophylaxis is not recommended for patients
undergoing total hip replacement surgery.
C
6.1.1
4. Use graduated compression stockings or intermittent pneumatic compression following
total hip replacement until the patient is fully mobile, whether or not pharmacological
thromboprophylaxis is used.
If possible, use graduated compression stockings with a foot pump where pharmacological
thromboprophylaxis is not used.
B
6.1.1
B
6.1.1
5. Unfractionated heparin is not recommended for thromboprophylaxis following total hip
replacement. Only use unfractionated heparin if recommended thromboprophylactic
options are not available.
B
6.1.1
6. Aspirin is not recommended as the sole agent for thromboprophylaxis following total
hip replacement.
C
6.1.1
7. Warfarin is not recommended for thromboprophylaxis following total hip replacement
except where used for therapeutic reasons.
C
6.1.1
C
6.1.1
B
6.1.1
Grade
Evidence
in section
GPP
6.1.2
2. In the absence of contraindications, commence pharmacological thromboprophylaxis and
continue for up to 35 days for hip fracture surgery. Use one of the following:
• fondaparinux
• low molecular weight heparin.
B
B
6.1.2
6.1.2
3. If low molecular weight heparin is used, consider the addition of low dose aspirin.
B
6.1.2
4. Aspirin is not recommended as the sole agent for thromboprophylaxis following hip
fracture surgery.
B
6.1.2
Recommendations by clinical procedure
Total hip replacement
In these cases use adjusted therapeutic doses for four to five weeks.
8. In patients with heparin-induced thrombocytopaenia, use heparinoids such as danaparoid as an
alternative thromboprophylactic option.
Hip fracture surgery
1. Use thromboprophylaxis for all patients admitted to hospital for hip fracture surgery.
Grade
Evidence
in section
5. Unfractionated heparin is not recommended for thromboprophylaxis following hip
fracture surgery.
B
6.1.2
6. Warfarin is not recommended for thromboprophylaxis following hip fracture surgery.
B
6.1.2
7. If pharmacological thromboprophylaxis is contraindicated or not available, use one of the
following until the patient is fully mobile:
• foot pump
• intermittent pneumatic compression.
C
6.1.2
8. In patients with heparin-induced thrombocytopaenia, use heparinoids such as danaparoid as an
alternative thromboprophylactic option.
B
6.1.2
Grade
Evidence
in section
1. Use thromboprophylaxis for all patients admitted to hospital for total knee replacement.
GPP
6.1.3
postoperatively and continue for up to 14 days following total knee replacement surgery.
• fondaparinux
• rivaroxaban
• dabigatran etexilate.
A
B
B
B
6.1.3
6.1.3
6.1.3
6.1.3
3. Use one of the following whether or not pharmacological thromboprophylaxis is used, until the
patient is fully mobile:
• foot pump
C
6.1.3
4. Aspirin alone is not recommended for thromboprophylaxis following total knee replacement.
C
6.1.3
5. Warfarin is not recommended for thromboprophylaxis following total knee replacement.
B
6.1.3
B
6.1.4
GPP
6.1.4
A
6.1.5
Hip fracture surgery (cont)
Total knee replacement
Knee arthroscopy
1. Thromboprophylaxis is not recommended following knee arthroscopy.
Consider thromboprophylaxis for patients with additional VTE risk factors, in the absence
of contraindications.
Lower leg fractures and injuries
1. Use low molecular weight heparin for all patients admitted to hospital with a lower leg fracture
or injury with immobilisation in a brace or a plaster cast. Thromboprophylaxis should be
continued for the entire period of immobilisation.
13
Grade
Evidence
in section
GPP
6.1.6
B
A
6.1.6
6.1.6
3. Use graduated compression stockings for all general surgical patients, whether or not
pharmacological thromboprophylaxis is used, until the patient is fully mobile.
B
6.1.6
4. If recommended thromboprophylaxis is contraindicated or not available, use a foot pump
following general surgery, until the patient is fully mobile.
C
6.1.6
1. Consider thromboprophylaxis for patients admitted to hospital for urological surgery based on
an assessment of the patient’s risk of VTE and bleeding.
GPP
6.1.7
Grade
Evidence
in section
1. Use thromboprophylaxis for all patients admitted to hospital for major gynaecological surgery.
GPP
6.1.8
postoperatively and continue for up to one week or until the patient is fully mobile following
major gynaecological surgery. Use one of the following:
• unfractionated heparin.
B
6.1.8
GPP
6.1.8
C
6.1.8
GPP
6.1.9
postoperatively with low molecular weight heparin and continue for at least five to nine days.
B
6.1.9
3. Fondaparinux is not recommended for thromboprophylaxis following major abdominal surgery.
C
6.1.9
4. Use graduated compression stockings for all patients following abdominal surgery, whether or
not pharmacological thromboprophylaxis is used, until the patient is fully mobile.
B
6.1.9
General surgery
1. Use thromboprophylaxis for all patients admitted to hospital for general surgery.
major general surgery. Use one of the following:
Urological surgery
Gynaecological surgery
3. Consider the additional use of graduated compression stockings or other mechanical
thromboprophylaxis following major gynaecological surgery, especially if pharmacological
thromboprophylaxis is contraindicated.
4. Warfarin is not recommended for thromboprophylaxis following major gynaecological surgery.
Abdominal surgery
1. Use thromboprophylaxis for all patients admitted to hospital for major abdominal surgery.
Grade
Evidence
in section
GPP
6.1.0
cardiac, thoracic, or vascular surgery. Use one of the following:
B
6.1.0
3. Use one of the following for all patients following cardiac, thoracic, or vascular surgery, whether
or not pharmacological thromboprophylaxis is used, until the patient is fully mobile:
• graduated compression stockings
C
6.1.0
Grade
Evidence
in section
A
6.1.11
GPP
6.1.11
3. Where pharmacological thromboprophylaxis is appropriate and not contraindicated, use low
molecular weight heparin or unfractionated heparin.
B
6.1.11
4. Consider the use of graduated compression stockings following neurosurgery (alone or in
combination with pharmacological thromboprophylaxis).
C
6.1.11
1. Use thromboprophylaxis for all patients admitted to hospital for trauma surgery or spinal surgery.
GPP
6.1.12
2. In the absence of contraindications, use a foot pump from hospital admission with the addition of
low molecular weight heparin five days after admission for trauma patients undergoing surgery.
C
6.1.12
Grade
Evidence
in section
A
6.2
GPP
6.2
Cardiac, thoracic and vascular surgery
1. Use thromboprophylaxis for all patients admitted to hospital following cardiac, thoracic or
vascular surgery.
Neurosurgery
1. Use intermittent pneumatic compression following neurosurgery, until the patient is fully mobile.
2. Use pharmacological thromboprophylaxis with extreme caution in patients following
neurosurgery, due to the high risk of bleeding.
Trauma surgery or spinal surgery
5.2 Anaesthesia
Recommendation
1. Consider central neural blockade as an alternative to general anaesthesia if feasible.
If central neural blockade is used there is a risk of developing an epidural haematoma. To minimise
this risk, timing of pharmacological thromboprophylaxis should be carefully planned and discussed
in advance with the anaesthetist.
15
5.3Medical patients
Grade
Evidence
in section
B
6.3.1
GPP
6.3.1
3. Where thromboprophylaxis is appropriate and not contraindicated, use low molecular weight
heparin for patients with ischaemic stroke.
B
6.3.1
If low molecular weight heparin is contraindicated or not available, use unfractionated heparin.
B
6.3.1
1. Use thromboprophylaxis for patients admitted to hospital for myocardial infarction, where full
anticoagulation is not in use.
C
6.3.2
2. In the absence of contraindications, use unfractionated heparin for thromboprophylaxis following
myocardial infarction.
C
6.3.2
GPP
6.3.3
B
6.3.3
Grade
Evidence
in section
1. Use thromboprophylaxis for all cancer patients undergoing general surgical procedures
including abdominal or pelvic surgery or neurosurgery, provided there are no contraindications.
Commence pharmacological thromboprophylaxis postoperatively and continue for at least
seven to 10 days following major general surgery for cancer. Use one of the following:
• unfractionated heparin
GPP
6.4
2. Consider using extended thromoprophylaxis with low molecular weight heparin for up to
28 days after major abdominal or pelvic surgery for cancer, especially in patients who are obese,
slow to mobilise or have a past history of VTE.
GPP
6.4
3. In the absence of other significant risk factors, thromboprophylaxis is not recommended for
cancer patients undergoing head and neck surgery.
GPP
6.4
4. In non-surgical cancer patients in the absence of contraindications, commence
thromboprophylaxis on admission and continue until discharge. Use one of the following:
GPP
6.4
5. For both non-surgical and surgical cancer patients, use graduated compression stockings if
pharmacological thromboprophylaxis is contraindicated.
GPP
6.4
Recommendations by medical condition
Stroke
1. Consider the use of thromboprophylaxis for all patients admitted to hospital with ischaemic
stroke based on an assessment of the patient’s degree of immobility and risk of bleeding.
2. Pharmacological thromboprophylaxis is not recommended for haemorrhagic stroke patients due
to the risk of intracranial bleeding.
Myocardial infarction
General medical
1. Consider the use of thromboprophylaxis for patients admitted to hospital for medical conditions
based on an assessment of the patient’s risk of VTE and bleeding.
2. In the absence of contraindications, use one of the following:
5.4 Cancer patients
Recommendations for surgical and non-surgical cancer patients
5.5 Pregnancy and childbirth
Grade
Evidence
in section
1. Minimise immobilisation of women during pregnancy, labour and the puerperium and ensure
adequate hydration at all times.
GPP
6.5
2. All women who deliver by caesarean section are at increased risk of VTE and should be
mobilised promptly after surgery.
GPP
6.5
3. Where pharmacological thromboprophylaxis is appropriate and not contraindicated, use low
molecular weight heparin after caesarean delivery for five to seven days, or until the patient is
fully mobile.
GPP
6.5
4. Extend pharmacological thromboprophylaxis with low molecular weight heparin or adjusted
dose warfarin to six weeks for high-risk women, after caesarean or vaginal delivery.
GPP
6.5
5. Consider the use of graduated compression stockings if pharmacological thromboprophylaxis is
contraindicated or not used.
GPP
6.5
6. Consider the use of intermittent pneumatic compression during caesarean and in the
postoperative period for up to 24 hours.
GPP
6.5
Recommendations
17
rivaroxaban
warfarin
aspirin
gcs


  
x
x
± 
x


–

x
+
–


Total knee replacement
–

–
  
x
x
–


Knee arthroscopy
–
x
–
–
–
–
–
–
–
–
–
Lower leg fractures and injuries
–

–
–
–
–
–
–
–
–
–
General surgery


–
–
–
–
–
–
±
–

Urological surgery
x
–
–
–
–
–
–
–
–
–
–
Gynaecological surgery


–
–
–
–
x
–
± ±
Abdominal surgery
–

–
–
–
x
–
–

–
–
Cardiac, thoracic and vascular surgery


–
–
–
–
–
–


–
Neurosurgery


–
–
–
–
–
–
± 
–
Trauma surgery and spinal surgery
–
–
–
–
–
–
–
–
–
Ischaemic stroke


–
–
–
–
–
–
–
–
–
Myocardial infarction

–
–
–
–
–
–
–
–
–
–
Mixed medical


–
–
–
–
–
–
–
–
–
Cancer
–
–
–
–
–
–
–
–
–
–
–
Pregnancy and childbirth
–
–
–
–
–
–
–
–
–
–
–


at
day 5
–
Evidence supports use of this agent for thromboprophylaxis for this clinical category
±
Evidence supports use of this agent for thromboprophylaxis with or without other
thromboprophylactic agents for this clinical category
+
Evidence supports use of this agent for thromboprophylaxis only in addition with another
thromboprophylactic agent for this clinical category
x
Evidence does not support use of this agent for thromboprophylaxis for this clinical category
x
This agent is not recommended for this clinical category
–
There is no evidence about this form of thromboprophylaxis for this clinical category
foot pump
heparanoid
x
ipc
Lmwh
dabigatran
UFH
fondaparinux
Summary of availability of evidence for use of thromboprophylactic
agents by clinical category

use with
GCS
±
+
use with
LMWH
6Evidence and recommendation
6.1 Surgical patients – Evidence and recommendations for
VTE prophylaxis
6.1.1Total hip replacement
This section summarises the evidence from systematic reviews and individual trials considered for
the prevention of VTE in patients undergoing total hip replacement. Full evidence tables on which
these summaries are based are provided in Appendix D (tables 1-30, 61, 62 and 65).
The recommendations given below were based on the body of evidence, with consideration of
the strength of evidence, consistency across studies, likely clinical impact, and generalisability
and applicability of study findings in the Australian context. Details of this process are provided
in Appendix B. Explanations are given for those recommendations that are inconsistent with the
corresponding evidence summaries. Where necessary, some additional explanation has been
provided to help interpret the recommendations in light of the evidence presented.
No recommendations were made where the evidence was of poor quality or not relevant to the
current Australian healthcare context. Difficulties in interpreting the evidence are summarised in
section 3.
Good Practice Points (GPP) are consensus-based, and are provided where the available evidence
was inadequate or could not be applied in the Australian healthcare context.
VTE
prophylactic
agent
Evidence summary - thromboprophylaxis for total hip replacement patients
Level
References
Rivaroxaban
In two multi-centre international RCTs, rivaroxaban (10mg orally once per day
for 35 days) was more effective at reducing the occurrence of DVT than LMWH
(40mg once per day, either for 35 days or 14 days). There were no significant
differences in the rates of PE or adverse events, including death, between the
rivaroxaban and LMWH arms.
I
46,47
Dabigatran
etexilate
In one multi-centre international RCT, there were no significant differences in rates
of DVT or PE with dabigatran etexilate (220mg or 150mg) compared with LMWH
(40mg daily). There were no significant differences in the rates of adverse events
between the two groups.
I
48
Fondaparinux
In two RCTs of patients who received either LMWH (40mg once per day)
or fondaparinux (2.5mg once daily) for up to nine days, the group receiving
fondaparinux had significantly lower rates of VTE or DVT. However, fondaparinux
was associated with significantly higher rates of major bleeding than LMWH.
I
49,50
19
VTE
prophylactic
agent
Level
References
Pooling of seven RCTs comparing LMWH with no treatment showed significantly
fewer asymptomatic DVTs with LMWH. There were no differences in the
occurrence of adverse events, such as wound haematoma or major bleeding,
between the groups receiving LMWH and no treatment. Various doses of LMWH
were used across the RCTs.
I
51-57
In a systematic review of six RCTs, extended duration of prophylaxis with LMWH
(to 28–35 days postoperatively) resulted in significantly lower rates of both
proximal and symptomatic DVT and lower rates of PE compared with extended
placebo. Extended duration of prophylaxis was not associated with an increased
rate of adverse events.
I
58
In one RCT, there was no advantage in preoperative administration of LMWH
compared with postoperative administration. A further three RCTs investigated
dosage effects of LMWH. From this evidence, higher doses of LMWH reduced the
rate of asymptomatic and distal DVT, but did not affect the rate of symptomatic or
proximal DVT.
I
59-62
LMWH
or UFH
Across six RCTs, rates of asymptomatic DVT did not differ between patients
receiving LMWH or UFH. However, in three of the six RCTs, patients receiving
LMWH had lower rates of proximal DVT. The occurrence of adverse events,
including bleeding, did not differ between LMWH and UFH groups.
I
63-68
GCS
Pooling of eight RCTs showed significantly lower rates of asymptomatic DVT when
total hip replacement patients wore graduated compression stockings compared
with no treatment. Graduated compression stockings were shown to have an
additional benefit when added to effective pharmacological prophylaxis (however,
not when added to fondaparinux). 69
I
51,70-76
IPC
In one RCT of patients not on effective pharmacological prophylaxis, significantly
fewer asymptomatic DVT were detected in the intermittent pneumatic
compression (IPC) group compared with the group receiving no treatment.77 In
one small RCT of patients receiving IPC or LMWH, rates of proximal DVT did not
differ between the groups.78 In two RCTs, continuous enhanced circulation therapy
was the form of IPC evaluated.79,80 These trials were excluded from analysis as the
method of thromboprophylaxis is not available in Australia.
I
77-80
GCS or IPC
Two small RCTs comparing graduated compression stockings with IPC were
inconclusive. One RCT suggested a benefit of adding IPC to LMWH compared
with adding GCS to LMWH for asymptomatic DVT but not other outcomes. 81
I
81,82
Foot pump
In one RCT of patients not receiving pharmacological prophylaxis, the addition of
a foot pump to graduated compression stockings was more effective in preventing
VTE than the stockings alone. Two small unblinded studies comparing LMWH with
a foot pump were inconclusive.
I
83-85
Danaparoid
In two RCTs, danaparoid was more effective in preventing DVT (including proximal
DVT) than UFH, or no treatment.
I
86,87
Aspirin
In two RCTs there were no significant differences in the rates of proximal DVT,
distal DVT, PE and the rates of adverse events between groups given aspirin or
no treatment.
I
88,89
LMWH
VTE
prophylactic
agent
Warfarin
Level
References
In two RCTs, there were no differences in the rate of DVT and the rates of
adverse events between groups given warfarin and no treatment.
I
90,91
In three RCTs, there was a small but non-significant difference in the rate of DVT
between groups given warfarin or aspirin; this favoured warfarin.
I
92-94
In two RCTs, adjusted therapeutic doses of warfarin were more effective than fixed,
low-dose warfarin in preventing VTE.
I
95,96
In one RCT of patients receiving standard therapeutic doses of warfarin, extended
duration (28-35 days) was more effective than shorter-term administration of
warfarin for preventing VTE.
I
97
RCTs comparing IPC with warfarin were not applicable to the Australian
healthcare context.
I
98-101
Discussion about the evidence and basis for recommendations for total hip replacement
Patients undergoing total hip replacement are in the highest risk category for VTE, on the basis of
the procedure itself,30,102 and in the absence of thromboprophylaxis, risk of VTE is high following
total hip replacement.103,104
Recommendation
Grade
1. Use thromboprophylaxis for all patients admitted to hospital for total hip replacement.
GPP
Low molecular weight heparin, fondaparinux, rivaroxaban and dabigatran etexilate are all effective
VTE prophylactic agents following total hip replacement. RCTs have shown that rivaroxaban
(10mg daily) or fondaparinux (2.5mg daily) significantly reduced VTE compared with low
molecular weight heparin46,47,49,50 while the effectiveness of dabigatran etexilate (220mg or 150mg
daily) and low molecular weight heparin was similar.48 Importantly, the rates of adverse events,
including bleeding were similar for rivaroxaban and dabigatran etexilate compared with low
molecular weight heparin. Low molecular weight heparin was more effective than unfractionated
heparin63-68 or warfarin.105-107
The choice of thromboprophylactic agent to be used after total hip replacement should be based
on availability, cost and individual patients’ risk characteristics and preferences.
Rivaroxaban and dabigatran etexilate are oral thromboprophylactic agents that were registered by
the Therapeutic Goods Administration and became available in Australia in late 2008. Post-marketing
surveillance for adverse events has not been completed for rivaroxaban or dabigatran, so both should
be used with caution. The lack of information on post-marketing surveillance for rivaroxaban and
dabigatran, along with the number of available RCTs influenced the grading of the recommendation.
When this information becomes available, the recommendation should be reviewed.
In RCTs where low molecular weight heparin was compared with fondaparinux for nine days,
fondaparinux significantly reduced DVT but also caused significantly more bleeding.49,50 Fondaparinux
should be used with caution as it may cause bleeding, particularly in those weighing less than 50kg,
in the frail, the elderly and those with renal impairment.
21
Duration of thromboprophylaxis: The risk of late-occurring DVT following total hip replacement
remains high until at least day 35 after surgery.108 In trials of extended duration low molecular
weight heparin, thromboprophylaxis was more effective when administered for up to 35 days
after surgery than for shorter durations, with no significant increase in bleeding.58 Therefore,
pharmacological prophylaxis has been recommended for up to 35 days following total hip
replacement surgery.
Timing of thromboprophylaxis: Preoperative administration of pharmacological prophylaxis was
shown to provide no additional benefit compared with postoperative administration.59 Based on
this and the practical difficulties of preoperative administration in the context of the increasing
frequency of same-day admissions, all pharmacological thromboprophylaxis should only be
administered postoperatively following total hip replacement.
Dosage of thromboprophylaxis: In RCTs comparing low molecular weight heparin with no treatment,
there were various doses of low molecular weight heparin used across the trials. If low molecular
weight heparin is chosen for thromboprophylaxis, it should commence postoperatively and dosage
should follow manufacturer’s instructions.
Recommendation
Grade
2. In the absence of contraindications, commence pharmacological thromboprophylaxis postoperatively and
continue for up to 35 days following total hip replacement surgery. Use one of the following:
• fondaparinux#
• rivaroxaban*
• dabigatran etexilate.*
3. Preoperative administration of thromboprophylaxis is not recommended for patients undergoing total
hip replacement surgery.
A
B
B
B
C
* Rivaroxaban and dabigatran etexilate are newly approved agents and post-marketing surveillance on adverse events is not
yet available.
#Use fondaparinux with caution as it may cause bleeding in those weighing less than 50kg, in the frail, the elderly and those
with renal impairment.
Mechanical methods reduce the risk of VTE following total hip replacement70-75,83 and are
recommended whether or not pharmacological prophylaxis is used. In one RCT of patients wearing
graduated compression stockings and not on effective pharmacological prophylaxis, the addition
of a foot pump was associated with a significant decrease in the rate of DVT (including proximal
DVT).83 Graduated compression stockings or intermittent pneumatic compression do not increase
the risk of bleeding. The effectiveness of graduated compression stockings can be increased if
used in conjunction with a foot pump. RCTs comparing graduated compression stockings with
intermittent pneumatic compression were inconclusive.81,82
Intermittent pneumatic compression significantly reduced the occurrence of asymptomatic DVT
compared with no treatment77 and there was some suggestion from a small study from 1996 that
intermittent pneumatic compression could be used as an alternative to low molecular weight
heparin.78 Studies comparing foot pump with low molecular weight heparin were inconclusive84,85
but there was some suggestion that intermittent pneumatic compression added to low molecular
weight heparin reduces asymptomatic DVT.81 Intermittent pneumatic compression is also an option
if pharmacological prophylaxis is contraindicated.
Recommendation
Grade
4. Use graduated compression stockings or intermittent pneumatic compression following total hip replacement
until the patient is fully mobile, whether or not pharmacological thromboprophylaxis is used.
If possible, use graduated compression stockings with a foot pump where pharmacological
thromboprophylaxis is not used.
B
B
In two RCTs, the rates of VTE did not differ between groups of patients given aspirin and no
thromboprophylactic treatment following total hip replacement.88,89 Consequently, aspirin is not
recommended as the sole form of thromboprophylaxis. Similarly, the rates of VTE did not differ
between groups of patients given warfarin and no treatment.90,91 Warfarin may be used by some
patients for therapeutic reasons other than thromboprophylaxis. In the cases where warfarin use
is unavoidable, adjusted therapeutic doses are more likely to be effective in preventing VTE than
fixed low-dose warfarin.95,96
Given the availability of more efficacious options, warfarin, unfractionated heparin and aspirin
should not be used for thromboprophylaxis following total hip replacement.
Recommendation
Grade
5. Unfractionated heparin is not recommended for thromboprophylaxis following total hip replacement. Only
use unfractionated heparin if recommended thromboprophylactic options are not available.
B
6. Aspirin is not recommended as the sole agent for thromboprophylaxis following total hip replacement.
C
7. Warfarin is not recommended for thromboprophylaxis following total hip replacement except where used
for therapeutic reasons. In these cases, use adjusted therapeutic doses for four to five weeks.
C
C
Heparin-induced thrombocytopaenia (HIT) is the development of thrombocytopaenia
(low platelet counts) due to the administration of the anticoagulant heparin, either in its
unfractionated or low molecular weight form. Upon diagnosis of HIT, treatment of HIT requires
both protection from thrombosis and choice of a thromboprophylactic agent that will not reduce
the platelet count further. The heparinoid danaparoid does not reduce the platelet count. In two
RCTs of patients undergoing total hip replacement, the heparinoid danaparoid was more effective
for thromboprophylaxis than unfractionated heparin or no treatment.86,87 Therefore, in patients
with heparin-induced thrombocytopaenia, heparinoids such as danaparoid are an alternative
thromboprophylactic option following total hip replacement surgery.
Recommendation
Grade
8. In patients with heparin-induced thrombocytopaenia, use heparinoids such as danaparoid as an alternative
thromboprophylactic option.
B
23
6.1.2 Hip fracture surgery
This section summarises the evidence from systematic reviews and individual trials for the
prevention of VTE in patients undergoing surgery for hip fracture. Full evidence tables on which
these summaries are based are provided in Appendix D (tables 31-49).
The recommendations were based on the body of evidence, with consideration of the strength of
evidence, consistency across studies, likely clinical impact, and generalisability and applicability
of study findings in the Australian context. Details of this process are provided in Appendix B.
Explanations are given for those recommendations that are inconsistent with the corresponding
evidence summaries. Where necessary, some additional explanation has been provided to help
interpret the recommendations in light of the evidence presented.
No recommendations were made where the evidence was of poor quality or not relevant to
the current Australian healthcare context. Difficulties in interpreting the evidence are summarised
in section 3.
VTE
prophylactic
agent
Evidence summary – thromboprophylaxis for hip fracture surgery patients
Level
References
In one RCT comparing fondaparinux with LMWH, there were significantly lower
rates of total VTE and DVT (including proximal DVT) in patients receiving fondaparinux
(and no differences in bleeding). There was no difference in the rates of PE between
the two groups.
I
109
In one RCT, there were significantly lower rates of VTE (including proximal DVT and
PE) in patients receiving fondaparinux for between 31 to 39 days compared with up
to eight days postoperatively. There was no difference in the occurrence of bleeding.
I
110
LMWH
A systematic review of five RCTs showed that rates of DVT (including proximal
DVT) were lower in patients receiving LMWH than in those receiving no
treatment. There was no significant difference in the rates of adverse events such
as wound haematoma, wound infections or death. The trials on preoperative versus
postoperative administration of LMWH were inconclusive.
I
111
Foot pump or
IPC
In an RCT of patients undergoing hip fracture surgery and not on effective
pharmacological prophylaxis, patients with foot pumps or IPC devices applied had
lower rates of DVT and PE than those receiving no treatment. There were no direct
comparisons between IPC and foot pump. In a separate RCT, rates of VTE did not
differ between patients on IPC in addition to LMWH compared with those on
LMWH alone.112
I
111,112
Danaparoid
Rates of DVT were lower in patients receiving danaparoid than those receiving
aspirin113 or warfarin.114 There was no difference in adverse events.
I
113,114
Warfarin
In four RCTs, patients receiving warfarin had lower rates of DVT than those receiving
aspirin or no treatment. In two of the four RCTs that reported on major bleeding,
there was no significant difference in the occurrence of major bleeding between
warfarin and no treatment.115,116
I
115-118
Aspirin
In the pulmonary embolism prevention trial (PEP), patients receiving aspirin
(160mg/day) along with other thromboprophylactic agents LMWH or UFH or
GCS, had lower rates of VTE than those who did not receive the added aspirin.
I
89
Fondaparinux
VTE
prophylactic
agent
Evidence summary – thromboprophylaxis for hip fracture surgery patients
Level
References
UFH
In a systematic review that included 10 RCTs, there were significantly lower rates of
DVT. No significant differences for any PE however for causes of death other than PE,
this just reached statistical significance in favour of no treatment. From the RCTs that
compared UFH with LMWH, there was insufficient evidence to recommend one in
preference to the other.
I
111
GCS
One RCT compared GCS plus fondaparinux with fondaparinux alone. This evidence
was discounted as it was a sub-group analysis with very few patients.
I
69
Discussion about the evidence and basis for recommendations for hip fracture surgery
Patients undergoing hip fracture surgery are in the highest risk category for VTE, on the basis of
the procedure itself30,102,119 and in the absence of thromboprophylaxis, reported rates of VTE are
high following surgery for hip fracture.102,104 Thromboprophylaxis has been shown to reduce the
risk of PE and mortality.120 Therefore, all patients admitted to hospital for surgery for hip fracture
should receive thromboprophylaxis following surgery.
Recommendation
Grade
1. Use thromboprophylaxis for all patients admitted to hospital for hip fracture surgery.
GPP
Whilst low molecular weight heparin,111 unfractionated heparin,111 warfarin115-118 and fondaparinux109
were all effective in preventing VTE, only low molecular weight heparin and fondaparinux are
recommended for thromboprophylaxis following hip fracture surgery. Warfarin has largely been
replaced by more practical and safer options for thromboprophylaxis. Warfarin requires close
monitoring and therapeutic dose adjustment, making it relatively costly. In addition, a failure to
maintain the appropriate level of anticoagulation with warfarin exposes the patient to an increased
risk of thrombosis or bleeding.
One RCT showed that fondaparinux significantly reduced DVT (including proximal DVT) in
preference to low molecular weight heparin for thromboprophylaxis following hip fracture
surgery.109 However, fondaparinux should be used with caution as it may cause bleeding
particularly in patients weighing less than 50kg, the frail, the elderly and those with renal
impairment. In one trial of hip fracture surgery patients, extended use of fondaparinux to between
31 and 39 days compared with eight days significantly reduced DVT and PE rates (with no
significant increase in bleeding).121 From this evidence, fondaparinux should be commenced
six to eight hours after surgery, and administered for 31 to 39 days (2.5mg once daily).
If low molecular weight heparin is chosen for thromboprophylaxis, it should commence
postoperatively and dosage should follow manufacturer’s instructions (as the dosages of low
molecular weight heparin varied across the RCTs considered).
The choice of thromboprophylactic agent to be used after total hip replacement should be based
25
Recommendation
Grade
2. In the absence of contraindications, commence pharmacological thromboprophylaxis and continue for up to
35 days for hip fracture surgery. Use one of the following:
• fondaparinux#
• low molecular weight heparin.
B
B
#Use fondaparinux with caution as it may cause bleeding in those weighing less than 50kg, in the frail, the elderly and those
In the pulmonary embolism prevention trial (PEP),89 low dose aspirin (160mg/day) added
to other more efficacious options such as low molecular weight heparin or unfractionated
heparin or graduated compression stockings following hip fracture surgery provided additional
thromboprophylactic benefit. Importantly, in this trial aspirin alone was not effective. Therefore,
low dose aspirin may be considered in combination with other more effective thromboprophylactic
agents following surgery for hip fracture.
Recommendation
Grade
3. If low molecular weight heparin is used, consider the addition of low dose aspirin.
B
4. Aspirin is not recommended as the sole agent for thromboprophylaxis following hip fracture surgery.
B
Recommendation
Grade
5. Unfractionated heparin is not recommended for thromboprophylaxis following hip fracture surgery.
B
6. Warfarin is not recommended for thromboprophylaxis following hip fracture surgery.
B
The use of either a foot pump or intermittent pneumatic compression is associated with a
significant reduction in the rates of DVT (including proximal DVT) and PE compared with no
treatment.111 The use of either is recommended if pharmacological prophylaxis is contraindicated
or not available following surgery for hip fracture. From one small study comparing intermittent
pneumatic compression and low molecular weight heparin, there was insufficient evidence
to support one in preference to another.122 There was no demonstration of benefit in adding
intermittent pneumatic compression to low molecular weight heparin.112
Recommendation
Grade
7. If pharmacological thromboprophylaxis is contraindicated or not available, use one of the following until the
patient is fully mobile:
• foot pump
B
Heparin-induced thrombocytopaenia (HIT) is the development of thrombocytopaenia (low platelet
counts) due to the administration of the anticoagulant heparin, either in its unfractionated or low
molecular weight form. Upon diagnosis of HIT, treatment of HIT requires both protection from
thrombosis and choice of a thromboprophylactic agent that will not reduce the platelet count
further. The heparinoid danaparoid does not reduce the platelet count. In two RCTs of patients
undergoing hip fracture surgery, the heparinoid danaparoid was more effective than warfarin114
or aspirin.89 Therefore, in patients with heparin-induced thrombocytopaenia, heparinoids such as
danaparoid are an alternative thromboprophylactic option following hip fracture.
Recommendation
Grade
8. In patients with heparin-induced thrombocytopaenia, use heparinoids such as danaparoid as an alternative
thromboprophylactic option.
B
6.1.3Total knee replacement
This section summarises the evidence from systematic reviews and individual trials for the
prevention of VTE in patients undergoing total knee replacement. Full evidence tables on which
these summaries are based are provided in Appendix D (tables 50-60).
The recommendations provided were based on the body of evidence, with consideration of
and applicability of study findings in the Australian context. Details of this process are given in
Appendix B. Explanations are given for those recommendations that are inconsistent with the
in section 3.
VTE
prophylactic
agent
Evidence summary – thromboprophylaxis for total knee replacement
surgery patients
Level
References
Rivaroxaban
In two RCTs rivaroxaban (10mg orally once per day for two weeks) was more
effective at reducing DVT (asymptomatic, symptomatic and distal DVT) than
LMWH (40mg subcutaneously once per day for two weeks). There was no
difference in non-fatal PE, death or bleeding between rivaroxaban and LMWH.
I
123,124
Fondaparinux
In one RCT fondaparinux was more effective at reducing VTE and DVT (including
proximal DVT) than LMWH; however fondaparinux caused significantly more
major bleeding than LMWH.
I
125
Dabigatran
Etexilate
In two RCTs there was no significant difference in rates of DVT or PE with
dabigatran etexilate (220mg or 150mg) compared with LMWH (40mg daily).
There was no significant difference in any adverse events between dabigatran
etexilate and LMWH.
I
126,127
27
VTE
prophylactic
agent
Evidence summary – thromboprophylaxis for total knee replacement
surgery patients
Level
References
LMWH, UFH
or IPC
In two RCTs there were significantly fewer DVT events (including proximal DVT)
in those receiving LMWH compared with no treatment or UFH 25,128 or IPC.129
There was no difference in adverse events for either UFH or IPC compared
with LMWH.
I
128-132
Foot pump
or IPC
In RCTs where patients were not on effective pharmacological prophylaxis, the
use of foot pump133 or intermittent pneumatic compression devices134 conferred
thromboprophylactic benefits compared with no treatment or aspirin;135,136
however there were no head-to-head comparisons of foot pumps versus IPC so
one cannot be recommended in preference to the other. There were a number of
studies that compared foot pump or IPC with pharmacological prophylaxis all of
which were inconclusive.137-139
I
133-139
Aspirin
In two RCTs intermittent pneumatic compression was more effective at reducing
DVT than low-dose aspirin (results for high dose aspirin not relevant as this
dosage would not be used in surgical patients). One RCT compared IPC plus
aspirin with IPC plus warfarin.139 This trial was excluded from analysis as it had a
small sample size and was underpowered.
I
135,136,139
Warfarin
In three RCTs, LMWH was more effective at reducing DVT than warfarin with
no significant difference in proximal DVT, PE or adverse events between LMWH
and warfarin.
I
140-142
In one RCT, there was no thromboprophylactic benefit in preoperative
warfarin dosing.
I
143
Discussion about the evidence and basis for recommendations for total knee replacement
Patients undergoing surgery for total knee replacement are in one of the highest risk categories for
VTE, on the basis of the procedure itself. 30,102,119 Therefore, all patients admitted to hospital for total
knee replacement surgery should receive thromboprophylaxis following surgery.
Recommendation
Grade
1. Use thromboprophylaxis for all patients admitted to hospital for total knee replacement.
GPP
Low molecular weight heparin,130,131 fondaparinux,125 rivaroxaban123,124 and dabigatran etexilate126,127
are all effective VTE prophylactic agents following total knee replacement. RCTs have shown that
rivaroxaban123,124 or fondaparinux125 reduce VTE in preference to low molecular weight heparin,
while the effectiveness of dabigatran etexilate126,144 and low molecular weight heparin was similar.
Importantly, there was no difference in adverse events including bleeding for both rivaroxaban and
dabigatran etexilate compared with low molecular weight heparin. Low molecular weight heparin
reduced DVT significantly compared with unfractionated heparin128,132 effective at reducing DVT
(with no difference in proximal DVT or PE between the two agents).
Rivaroxaban and dabigatran etexilate are oral thromboprophylactic agents that were registered
by the Therapeutic Goods Administration and became available in late 2008. Post-marketing
surveillance for adverse events has not been completed for rivaroxaban or dabigatran, so
both should be used with caution. The lack of information on post-marketing surveillance for
rivaroxaban and dabigatran, along with the number of available RCTs influenced the grading
of the recommendation. When this information becomes available, the recommendation should
be reviewed.
While fondaparinux was more effective than low molecular weight heparin at reducing VTE
(including total and proximal DVT), it also resulted in significantly more bleeding.125 Fondaparinux
should be used with caution as it may cause bleeding particularly in those weighing less than 50kg,
in the frail, the elderly or those with renal impairment.
The choice of thromboprophylactic agent to be used after total knee replacement should be based
Duration of thromboprophylaxis: In the total knee replacement RCTs, low molecular weight
heparin was provided for a period of up to 14 days25,130 as was rivaroxaban.123 Therefore
pharmacological prophylaxis is recommended for a period of up to 14 days following total knee
replacement. It’s important to note that in the trial of fondaparinux compared with low molecular
weight heparin, prophylaxis was given for a period of between five to nine days145 and in the trials
of dabigatran etexilate, thromboprophylaxis was provided for between six to 10 days in one trial126
and 14 days in a second trial.144
Dosage of thromboprophylaxis: Some of the trials comparing low molecular weight heparin with
placebo used a 60mg daily dosage of low molecular weight heparin; this dose is not available
in Australia. Given the variability in dosages of the thromboprophylactic agents across the trials,
dosing of thromboprophylaxis is recommended according to manufacturer’s instructions following
surgery for total knee replacement.
Recommendation
Grade
continue for up to 14 days following total knee replacement surgery. Use one of the following:
• fondaparinux#
• rivaroxaban*
• dabigatran etexilate.*
A
B
B
B
* Rivaroxaban and dabigatran etexilate are newly approved agents and post-marketing surveillance on adverse events is not
yet available.
# Use fondaparinux with caution as it may cause bleeding in those weighing less than 50kg, in the frail, the elderly and those
Low molecular heparin was more effective at reducing DVT than intermittent pneumatic
compression129 while studies comparing foot pump with low molecular weight heparin were
inconclusive.137,138 Application of a foot pump133 or intermittent pneumatic compression134 was
shown to be beneficial in reducing DVT (including proximal DVT) compared with no treatment.
Intermittent pneumatic compression was also shown to significantly reduce DVT compared with
aspirin.135,136 Therefore, the use of aspirin has not been recommended. A further study evaluated
intermittent pneumatic compression plus low molecular weight heparin against intermittent
pneumatic compression plus aspirin;139 however, no conclusions could be drawn about the benefits
of combination pharmacological prophylaxis with intermittent pneumatic compression as this study
was small in sample size and was underpowered.
29
Recommendation
Grade
3. Use one of the following whether or not pharmacological thromboprophylaxis is used, until the patient is
fully mobile:
• foot pump
B
Recommendation
Grade
4. Aspirin alone is not recommended for thromboprophylaxis following total knee replacement.
C
Warfarin is not recommended for thromboprophylaxis following total knee replacement as it was
not shown to be effective in RCTs compared with low molecular weight heparin.141,142,146 One
study of warfarin timing suggests that preoperative warfarin dosing does not provide additional
thromboprophylactic benefit compared with postoperative dosing.143
Recommendation
Grade
5. Warfarin is not recommended for thromboprophylaxis following total knee replacement.
B
6.1.4 Knee arthroscopy
This section summarises evidence from systematic reviews and individual trials for the prevention
of VTE in patients undergoing knee arthroscopy. The full evidence tables on which these
summaries are based are provided in Appendix D (table 68).
in section 3.
VTE
prophylactic
agent
LMWH
Evidence summary - thromboprophylaxis for knee arthroscopy patients
Level References
In one systematic review of four RCTs 147 that compared LMWH with no
treatment or in a further RCT comparing LMWH with GCS,148 there were
significantly lower rates of asymptomatic and symptomatic DVT with LMWH.
There was no significant difference in the rates of PE between LMWH and no
treatment/GCS groups. There was significantly more bleeding with LMWH in all
five RCTs.
I
147,148
One RCT comparing extended duration LMWH with extended duration
placebo was not relevant as magnetic resonance venography was the diagnostic
technique employed and this is not a validated diagnostic technique for
detection of DVT.
I
149
Discussion about the evidence and basis for recommendations for knee arthroscopy
Arthroscopic knee surgery is generally regarded as a minimally invasive surgical procedure with
a low risk of VTE. However, some arthroscopic knee surgery may require prolonged use of a
tourniquet, extended surgical time, or can cause soft tissue or bone injury. All these factors increase
the risk of developing a thromboembolic event.
In trials of patients undergoing arthroscopic knee surgery, low molecular weight heparin was effective
at reducing the incidence of asymptomatic and symptomatic DVT compared with no treatment or
graduated compression stockings; however, this was primarily distal DVT.150 There was no difference
in the rates of PE (there was only one instance of PE in a treatment group from one of the included
studies).151 Importantly, instances of bleeding were significantly more common in patients receiving
low molecular weight heparin. These trials included arthroscopic procedures involving tourniquet time
of up to one hour,148 with no evidence available for prolonged arthroscopic knee surgery.
Based on the studies considered, although thromboprophylaxis may provide some benefit, this
was primarily for distal DVT and crucially, low molecular weight heparin caused significantly more
bleeding. Therefore, risk of prophylaxis outweighed benefits and in this case, thromboprophylaxis
is not recommended.
No studies on mechanical methods alone were available for arthroscopic knee surgery. In addition,
there was no evidence for thromboprophylaxis in patients undergoing arthroscopic knee surgery who
have additional VTE risk factors. A Good Practice Point (GPP) has been suggested for these patients.
Recommendation
Grade
1. Thromboprophylaxis is not recommended following knee arthroscopy.
Consider thromboprophylaxis for patients with additional VTE risk factors, in the absence of contraindications.
B
GPP
6.1.5Lower leg fractures and injuries with immobilisation
This section summarises evidence from a systematic review for the prevention of VTE in patients
with immobilisation of the lower leg in a plaster cast or brace due to fracture or injury. Full
evidence tables on which these summaries are based are provided in Appendix D (table 69).
31
in section 3.
VTE
prophylactic
agent
LMWH
Evidence summary – thromboprophylaxis for patients with
lower leg fractures and injuries with immobilisation
In a systematic review of six RCTs which included patients of
varying ages with either
• lower leg injuries with immobilisation or
• a lower limb in a plaster cast or brace (with or without surgery),
Level
References
I
45
there were significantly fewer instances of symptomatic VTE, DVT
and proximal DVT in patients that received LMWH compared with
no treatment. Major adverse events were rare in either the LMWH
or no treatment groups.
Discussion about the evidence and basis for recommendations for patients with immobilisation of the
lower leg in a plaster cast or brace due to fracture or injury
Immobilisation of the lower leg is a significant risk factor for the development of VTE.152,153 In a
systematic review of six RCTs, thromboprophylaxis with low molecular weight heparin for patients
with a leg immobilised in a cast or brace following lower leg fracture or injury significantly lowered
rates of both symptomatic and proximal DVT.45 Major adverse events such as haematoma, acute
bleeding, allergy and thrombocytopaenia were rare.
Patients who had a leg injury that had been immobilised in a plaster cast or brace, (regardless of
whether they were operated on, or whether the injury was a fracture or soft tissue damage) had
significantly reduced occurrence of DVT (proximal and distal) when treated with low molecular
weight heparin. There was no difference in PE with low molecular weight heparin. Importantly,
low molecular weight heparin was administered daily during the entire period of immobilisation.45
This suggests all patients who have had a lower leg fracture or injury (which involves
immobilisation in a brace or a plaster cast for a prolonged period) should receive low molecular
weight heparin for the entire period of immobilisation to prevent DVT.
Recommendation
Grade
1. Use low molecular weight heparin for all patients admitted to hospital with a lower leg fracture or injury with
immobilisation in a brace or a plaster cast. Thromboprophylaxis should be continued for the entire period of
immobilisation.
A
Mixed orthopaedic surgery (total hip replacement, total knee replacement and hip fracture surgery)
The summaries in the table below are of studies that could not be separated out by individual
orthopaedic procedure. They provide further support for the recommendations in the preceding
sections on total hip replacement, total knee replacement and hip fracture surgery. Full evidence
tables on which these summaries are based are provided in Appendix D (table 70-80).
VTE
prophylactic
agent
LMWH
Evidence summary – thromboprophylaxis for patients undergoing mixed
orthopaedic procedures
In two RCTs of patients undergoing one of the following orthopaedic surgical
procedures (total hip replacement, total knee replacement or hip fracture surgery),
VTE prophylaxis with LMWH was more effective if administered for an extended
duration (up to six weeks postoperatively).
Level
References
I
154,155
156
In a separate systematic review of 11 RCTs, LMWH was more effective than UFH at
reducing the incidence of proximal DVT and PE. No adverse events were measured
in this review.
Warfarin
In one RCT of patients undergoing total hip replacement or total knee
replacement, low intensity warfarin or low fixed dose warfarin was not effective for
thromboprophylaxis when compared with no treatment or UFH.
I
157,158
Aspirin
In two RCTs of patients undergoing total hip replacement or total knee replacement,
aspirin was not effective at reducing DVT (both proximal and distal), or PE when
compared with no treatment. No significant difference in adverse events.
I
88,89
UFH
In one systematic review of 21 RCTs of patients undergoing one of a range of
orthopaedic surgical procedures, there was a significantly lower rate of DVT when
UFH was used compared with no treatment. There was no significant difference in
major bleeds between UFH and no treatment.
I
159
33
6.1.6General surgery
of VTE in patients undergoing general surgical procedures. Full evidence tables on which these
summaries are based are provided in Appendix D (table 81-88).
No recommendations were made where the evidence was of poor quality or not relevant to the current
Australian healthcare context. Difficulties in interpreting the evidence are summarised in section 3.
VTE
prophylactic
agent
Evidence summary – thromboprophylaxis for general surgery patients
Level References
UFH
In a systematic review of 46 RCTs, there were significantly lower rates of DVT in
patients treated with unfractionated heparin (UFH) until discharge (up to one week
postoperatively) compared with those not receiving any treatment. There was no
significant difference in major bleeding between UFH and no treatment.
I
159
LMWH
or UFH
Across 10 RCTs comparing LMWH and UFH, both agents had similar effects in
preventing DVT and PE with no difference in adverse events other than lower
incidence of wound haematoma with LMWH (in seven of the trials which reported
this outcome).
I
160-170
GCS
Across 11 RCTs comparing graduated compression stockings (both thigh and knee
length) with no treatment, graduated compression stockings were more effective at
reducing DVT than no treatment (when used alone or in combination with heparin or
intermittent pneumatic compression).
I
171-181
In one RCT there was inconclusive evidence of benefit of graduated compression
stockings (GCS) compared with UFH. It was not possible to conclude that whether
UFH is better than GCS or vice versa.
I
182
Foot pump
In one RCT there were significantly lower rates of DVT in those patients treated
with a foot pump compared with those receiving no treatment. No PE events were
recorded in either group.
I
183
IPC
There were a number of RCTs that compared IPC with no treatment or UFH, all of
which were inconclusive.
I
184-190
Discussion about the evidence and basis for recommendations for general surgery
Patients undergoing major general surgery may be anaesthetised for a prolonged periods or have
limited postoperative mobility. These factors along with surgical procedure itself increase the risk of
VTE; therefore, thromboprophylaxis is recommended for all patients undergoing major general surgery.
Recommendation
Grade
1. Use thromboprophylaxis for all patients admitted to hospital for general surgery.
GPP
RCTs showed that low molecular weight heparin191-193 or unfractionated heparin159 both effectively
reduced the occurrence of DVT compared with no treatment. Compared with no treatment,
unfractionated heparin did not increase bleeding, however low molecular weight heparin caused
significantly more bleeding following general surgery. Low molecular weight heparin and
unfractionated heparin have similar effectiveness in preventing DVT;160-170 therefore the use of either
agent is recommended following general surgery. The duration of thromboprophylaxis with low
molecular weight heparin or unfractionated heparin was generally for up to one week in trials,
with various dosages used. Therefore thromboprophylaxis is recommended for up to one week,
with dosage according to manufacturer’s instructions.
Recommendation
Grade
2. In the absence of contraindications, commence pharmacological thromboprophylaxis postoperatively
and continue for up to one week or until the patient is fully mobile following major general surgery.
B
A
A number of RCTs evaluated the effectiveness of graduated compression stockings at reducing
venous thromboembolism following general surgery.171-181 These demonstrated that graduated
compression stockings can significantly reduce the occurrence of DVT. Graduated compression
stockings were shown to be beneficial as the sole prophylactic agent or in addition to heparin.
Most of these trials evaluated thigh-length graduated compression stockings; however two trials
used knee-length stockings.174,181 There were no direct comparisons available on the effectiveness
of knee versus thigh length graduated compression stockings. The application of graduated
compression stockings is recommended following general surgery, whether or not pharmacological
prophylaxis is used. Graduated compression stockings should be worn for as long as possible until
the patient is fully mobile. The choice of thigh or knee length graduated compression stockings
will be influenced by availability, compliance and patient preference.
Recommendation
Grade
3. Use graduated compression stockings for all general surgical patients, whether or not pharmacological
thromboprophylaxis is used, until the patient is fully mobile
B
The effectiveness of foot pump at preventing VTE following general surgery was evaluated in one
relatively small RCT from the early 1980’s.183 A foot pump applied bilaterally significantly reduced
DVT compared with providing no thromboprophylaxis following general surgery. A further study
evaluated the effectiveness of intermittent pneumatic compression compared with unfractionated
heparin. No conclusions could be drawn about the benefits of mechanical thromboprophylaxis
against pharmacological prophylaxis as this study was of poor quality.190
Recommendation
Grade
4. If recommended thromboprophylaxis is contraindicated or not available, use a foot pump following general
surgery, until the patient is fully mobile.
C
35
6.1.7Urological surgery
of VTE in patients undergoing urological surgical procedures. Full evidence tables on which these
current Australian healthcare context. Difficulties in interpreting the evidence are summarised
in section 3.
VTE
prophylactic
agent
Evidence summary – thromboprophylaxis for urological surgery patients
Level
References
UFH
In patients undergoing urological surgery, unfractionated heparin significantly
reduced the incidence of DVT compared with no treatment. However,
unfractionated heparin also resulted in significantly more major bleeding
compared with no treatment.
I
159
LMWH, IPC,
GCS, low
dose warfarin
There were a number of RCTs which compared a range of mechanical methods
of prophylaxis with other mechanical methods or pharmacological methods.
All of these RCTs were inconclusive.
I
194-197
LMWH
In one RCT of prostatectomy patients, there was inconclusive evidence of benefit
of LMWH compared with no treatment (due to lack of power of the study).
I
198
Discussion about the evidence and basis for recommendations for urological surgery
Many of the urological surgery RCTs used a broad categorisation of patients undergoing urological
surgery. It was not possible to separate the evidence from this heterogeneous group of patients.
Surgical procedures may have included prostatectomy, renal surgery or transurethral resection of
the prostate (TURP). This limited the ability to apply the evidence as these procedures present
different VTE and bleeding risk. For example, TURP may cause significant bleeding as the
surgery involves sharp dissection and electrocautery. This type of urological surgery procedure
may cause significantly more bleeding than renal surgery. In the absence of information about
benefits and harms for specific procedures, it was not possible to make a recommendation
regarding VTE prophylaxis following urological surgery. VTE prophylaxis should be an individual
clinician decision in patients undergoing urological surgery based on other VTE risk factors, with
consideration of the patient’s bleeding risk.
Recommendation
Grade
1. Consider thromboprophylaxis for patients admitted to hospital for urological surgery based on an
assessment of the patient’s risk of VTE and bleeding.
GPP
6.1.8Gynaecological surgery
of VTE in patients undergoing gynaecological surgical procedures. Full evidence tables on which
these summaries are based are provided in Appendix D (table 96-101).
in section 3.
VTE
prophylactic
agent
Evidence summary – thromboprophylaxis for gynaecological
surgery patients
Level
References
UFH
In two RCTs, UFH was more effective at reducing DVT compared with no
treatment following major gynaecological surgery.
I
199,200
LMWH or
UFH
Across five RCTs of major gynaecological surgery patients, LMWH and UFH
conferred similar benefits for the prevention of DVT. PE rates were only reported in
one trial, with no statistically significant difference between LMWH and UFH. In one
RCT there were significantly more transfusions in the LMWH group compared with
the UFH group. 201 In three RCTs 202-204 there was no significant difference between
LMWH and UFH for major haemorrhage or wound haematoma.
I
201-205
GCS
In one RCT there was no significant difference in rates of DVT between GCS and
no treatment.
I
206
IPC
In two RCTs there was no significant difference in DVT, proximal DVT or PE
between IPC and no treatment.
I
207,208
In one RCT of patients undergoing major gynaecological surgery for malignancy,
there was insufficient evidence to recommend IPC in preference to LMWH, or
vice versa. There were no significant differences in adverse events (blood loss or
thrombocytopaenia).
I
209
From one RCT there was no significant difference in DVT, proximal DVT or major
bleeding between warfarin and no treatment.
I
210
Warfarin
Discussion about the evidence and basis for recommendations for gynaecological surgery
Gynaecological surgery encompasses a range of surgical procedures from simple procedures to
complex curative surgery for cancer. Major gynaecological surgery increases the risk of VTE and
therefore thromboprophylaxis is recommended for all patients in this group. Thromboprophylaxis may
also be appropriate following other gynaecological procedures that increase the patient’s risk of VTE.
Recommendation
Grade
1. Use thromboprophylaxis for all patients admitted to hospital for major gynaecological surgery.
GPP
37
Pooling of data from two trials showed that unfractionated heparin reduced DVT compared with no
treatment (although this did not reach statistical significance).199,200 There was no significant difference
in adverse events between unfractionated heparin and no treatment. Low molecular weight heparin
and unfractionated heparin conferred similar thromboprophylactic benefit with no difference in adverse
events; therefore both are effective VTE prophylactic options following gynaecological surgery.201-205
Recommendation
Grade
continue for up to one week or until the patient is fully mobile following major gynaecological surgery. Use
one of the following:
B
There was no conclusive evidence regarding the effectiveness of graduated compression stockings
or intermittent pneumatic compression compared with no treatment following gynaecological
surgery.206-208 Mechanical methods of thromboprophylaxis may be considered for patients following
gynaecological surgery.
Recommendation
Grade
3. Consider the additional use of graduated compression stockings or other mechanical thromboprophylaxis
following major gynaecological surgery, especially if pharmacological thromboprophylaxis is contraindicated.
GPP
An RCT of fixed low dose warfarin demonstrated that warfarin provided no thromboprophylactic
benefit following gynaecological surgery.210 Therefore, the use of warfarin is not recommended
following major gynaecological surgery.
Recommendation
Grade
4. Warfarin is not recommended for thromboprophylaxis following major gynaecological surgery.
C
6.1.9Abdominal surgery
of VTE in patients undergoing abdominal surgical procedures. Full evidence tables on which these
current Australian healthcare context. Difficulties in interpreting the evidence are summarised
in section 3.
VTE
prophylactic
agent
Evidence summary – thromboprophylaxis for abdominal surgery patients
Level References
LMWH
In three RCTs, LMWH was effective at reducing the rate of DVT compared with
no treatment (when prophylaxis is begun 1-2 hours preoperatively and continued
for between five to nine days postoperatively). There was no difference in total
haemorrhage or wound haematoma in patients treated with LMWH compared
with placebo.
I
211-213
LMWH or
UFH
There were 23 RCTs comparing LMWH and UFH; LMWH was more effective at
reducing DVT (including symptomatic DVT) than UFH. There were no significant
differences in PE or adverse events including haemorrhage, wound haematoma,
transfusions or death between LMWH and UFH.
I
214-236
LMWH dose
In one RCT comparing doses of LMWH, standard doses of LMWH (5000IU)
were more effective than lower doses (2500IU); however, standard doses caused
significantly more major bleeding than lower doses.
I
237
LMWH
extended
duration
In one RCT of high risk cancer patients undergoing curative abdominal surgery,
extended duration LMWH (40mg LMWH for between 25 to 31 days post surgery)
was more effective at reducing rates of DVT than 40mg of LMWH administered for
up to 10 days. There was no difference in adverse events such as major bleeding or
death between the 10 day duration and extended duration LMWH groups.
I
238
Fondaparinux
In one RCT fondaparinux was more effective at reducing asymptomatic DVT than no
treatment or IPC alone. However, fondaparinux significantly increased major bleeding
complications compared with no treatment (with no difference in death rates).
I
239
In a separate trial comparing fondaparinux with LMWH, both agents were shown to
have similar effects on DVT and PE with no difference in bleeding or death between
the two groups.
240
GCS
In three RCTs there was a lower incidence of DVT among patients wearing thighlength graduated compression stockings compared with no treatment (stockings
worn alone or in combination with other more effective forms of prophylaxis such
as pharmacological prophylaxis). No adverse events were recorded in these RCTs.
There was inconclusive evidence from one RCT comparing GCS with UFH.181
I
181,
241-243
Aspirin
There was one RCT comparing aspirin with UFH. The aspirin and UFH doses used
in this trial were not applicable to the Australian healthcare setting.
I
244
IPC
There was inconclusive evidence from one RCT comparing IPC with UFH
(alone or in combination).
I
245
39
Discussion about the evidence and basis for recommendations for abdominal surgery
Major abdominal surgery increases the risk of VTE and therefore thromboprophylaxis is
recommended for all patients following major abdominal surgery.
Recommendation
Grade
1. Use thromboprophylaxis for all patients admitted to hospital for major abdominal surgery.
GPP
Fondaparinux239 or low molecular weight heparin211-213 were both effective VTE prophylactic options
compared with no treatment following abdominal surgery. However, fondaparinux significantly
increased major bleeding compared with no treatment, and therefore is not recommended.239
Across 23 RCTs comparing low molecular weight heparin with unfractionated heparin, low
molecular weight heparin significantly reduced DVT (including symptomatic DVT) compared with
unfractionated heparin, with no difference in adverse events including major haemorrhage.214-236
Therefore, low molecular weight heparin is recommended for thromboprophylaxis following
abdominal surgery.
Dosage and duration of thromboprophylaxis: In 1995, one trial examined optimal
thromboprophylactic dosage of low molecular weight heparin.237 This showed that whilst higher
doses were more effective for thromboprophylaxis than lower doses, higher doses also caused
significantly more bleeding. The dosage of low molecular weight heparin varied across the other
trials so dosing is recommended according to manufacturer’s instructions.
In one trial, the duration of low molecular weight heparin was investigated and it demonstrated
that thromboprophylaxis with low molecular weight heparin was more effective if extended to
between 25 and 31 days compared with 10 days. However, this study was carried out in a sub-set
of abdominal surgery patients that were considered high risk as they were undergoing curative
surgery for cancer.238 Therefore, thromboprophylaxis with low molecular weight heparin has been
recommended for between five to nine days for abdominal surgery patients.
Recommendation
Grade
2. In the absence of contraindications, commence pharmacological thromboprophylaxis postoperatively with
low molecular weight heparin and continue for at least five to nine days.
B
Recommendation
Grade
3. Fondaparinux is not recommended for thromboprophylaxis following major abdominal surgery.
C
Graduated compression stockings significantly reduced DVT compared with no treatment241-243 and
therefore have been recommended following abdominal surgery, whether or not pharmacological
prophylaxis is used. A further trial examined intermittent pneumatic compression compared with
unfractionated heparin;245 however no conclusions could be drawn from this study as the results
were inconclusive.
Recommendation
Grade
B
4. Use graduated compression stockings for all patients following abdominal surgery, whether or not
pharmacological thromboprophylaxis is used, until the patient is fully mobile.
6.1.10 Cardiac, thoracic and vascular surgery
of VTE in patients undergoing cardiac, thoracic or vascular surgical procedures. Full evidence
tables on which these summaries are based are provided in Appendix D (table 114-116).
in section 3.
VTE
prophylactic Evidence summary – thromboprophylaxis in cardiac, thoracic or vascular
agent
surgery patients
Level
References
LMWH or
UFH
In four RCTs no difference was detected in the rate of DVT between LMWH and
UFH. There were no differences in adverse events other than in one trial which
showed more wound haematomas in patients treated with UFH compared with
LMWH.246
I
246-249
IPC
In one RCT of cardiac surgery patients, thigh-length intermittent pneumatic
compression significantly reduced symptomatic PE when it was added to
thromboprophylaxis with heparin.
I
250
In one trial, thigh-length intermittent pneumatic compression (IPC) did not have
any additional benefit when applied to coronary artery bypass surgery patients
who were already receiving 325mg/day aspirin and wearing graduated compression
stockings.
I
251
In patients undergoing cardiothoracic surgery, there was no evidence of benefit of
using higher doses of UFH (7500BD) compared with lower doses of UFH (5000
BD).
I
252
UFH dose
Discussion about the evidence and basis for recommendations for patients undergoing cardiac,
thoracic or vascular surgery
Cardiac, thoracic or vascular surgery increases the risk of VTE and therefore thromboprophylaxis is
recommended for all patients following cardiac, thoracic or vascular surgery.
41
Recommendation
Grade
1. Use thromboprophylaxis for all patients admitted to hospital following cardiac, thoracic or vascular surgery.
GPP
RCTs demonstrated that low molecular weight heparin or unfractionated heparin are both effective
options for VTE prophylaxis following cardiac, thoracic or vascular surgery246-249 with no differences
in adverse events other than in one small trial which showed more wound haematomas in patients
treated with unfractionated hepain compared with low molecular weight heparin (this was in a
cancer patients undergoing thoracic surgery).246 Either low molecular weight heparin or unfractionated
heparin are recommended for thromboprophylaxis following cardiac, thoracic or vascular surgery.
The dosages and types of low molecular weight heparin varied across the trials so dosing is
recommended according to manufacturer’s instructions.
Recommendation
Grade
continue for up to one week or until the patient is fully mobile following cardiac, thoracic, or vascular surgery.
B
Thigh-length intermittent pneumatic compression significantly reduced symptomatic PE when
applied to patients receiving heparin.250 The application of intermittent pneumatic compression
did not provide any further thromboprophylactic benefit when applied to coronary artery bypass
patients that were wearing graduated compression stockings and receiving 325mg/day of aspirin.
The application of graduated compression stockings or intermittent pneumatic compression is
recommended following cardiothoracic surgery, whether or not pharmacological prophylaxis is
used (until the patient is fully mobile).
Recommendation
Grade
3. Use one of the following for all patients following cardiac, thoracic, or vascular surgery, whether or not
pharmacological thromboprophylaxis is used, until the patient is fully mobile:
• graduated compression stockings
C
6.1.11Neurosurgery
of VTE in patients undergoing neurosurgery. Full evidence tables on which these summaries are
based are provided in Appendix D (table 117-123).
in section 3.
VTE
prophylactic
agent
Evidence summary – thromboprophylaxis in neurosurgery patients
Level
References
IPC
Pooled data from seven RCTs showed there were significantly lower rates of
DVT in patients with intermittent pneumatic compression (mostly knee-length)
compared with no treatment. In three of these trials, there were significantly lower
rates of proximal DVT.253-255 No instances of PE were seen in either group across
three trials.253,255,256 In a separate RCT of LMWH versus IPC, this evidence was not
considered as the trial was terminated early.257
I
253-260
LMWH
In a systematic review of three trials,261 LMWH significantly reduced DVT (including
proximal DVT) compared with no treatment. There was no significant difference in
PE or adverse events such as bleeding or death.
I
261
UFH
In one RCT there were significantly lower rates of DVT in patients receiving UFH
compared with no treatment.262 There was no significant difference in bleeding
(including major bleeding) or death. No instances of clinically overt PE were seen
in either the UFH or no treatment groups. Two RCTs examined the effectiveness
of LMWH or UFH;263,264 there was insufficient evidence from these RCTs to draw
definitive conclusions.
I
262-264
GCS
In one RCT comparing the effects of using GCS compared with no treatment, there
was some suggestion of benefit on DVT of using GCS but this was not statistically
significant. There were no instances of fatal PE in either the GCS or no treatment
groups. One study which compared IPC with GCS in craniotomy patients was
excluded as it used an unreliable diagnostic technique.265
I
265,266
Discussion about the evidence and basis for recommendations for patients undergoing neurosurgery
Neurosurgery presents a high risk of VTE but the consequences of bleeding can be severe
following neurosurgery. Pharmacological prophylaxis should be used with caution in neurosurgery
patients depending on the risk of VTE and bleeding. Mechanical methods may be an appropriate
alternative. Intermittent pneumatic compression significantly reduced DVT (including proximal
DVT) compared with no treatment253-256,258-260 and therefore is recommended until the patient is
fully mobile.
43
Recommendation
Grade
1. Use intermittent pneumatic compression following neurosurgery, until the patient is fully mobile.
A
Recommendation
Grade
2. Use pharmacological thromboprophylaxis with extreme caution in patients following neurosurgery, due to
the high risk of bleeding.
GPP
Both low molecular weight heparin261 and unfractionated heparin262 significantly reduced DVT
following neurosurgery, with no difference in adverse events. Either low molecular weight heparin
or unfractionated heparin are recommended for thromboprophylaxis following neurosurgery.
Dosage and duration of thromboprophylaxis: As the balance between risk and benefit is
particularly important in this group of patients given the consequences of intracranial bleeding, the
duration of thromboprophylaxis should be an individual clinician decision based on the patient
risk assessment. The appropriateness of pharmacological thromboprophylaxis should be closely
monitored. Dosage is recommended according to manufacturer’s instructions.
Recommendation
Grade
3. Where pharmacological thromboprophylaxis is appropriate and not contraindicated, use low molecular
weight heparin or unfractionated heparin.
B
There was some suggestion of benefit of wearing graduated compression stockings for patients
following neurosurgery (however this was not statistically significant).266 Therefore, the use
of graduated compression stockings may be considered following neurosurgery. There was
insufficient evidence from one small trial to recommend graduated compression stockings in
preference to intermittent pneumatic compression (or vice versa).265
Recommendation
Grade
4. Consider the use of graduated compression stockings following neurosurgery (alone or in combination with
pharmacological thromboprophylaxis).
C
6.1.12Trauma surgery or spinal surgery
of VTE in patients undergoing surgery for trauma or spinal surgery. Full evidence tables on which
these summaries are based are provided in Appendix D (table 124-130).
in section 3.
VTE
prophylactic
agent
Evidence summary – thromboprophylaxis for trauma or spinal injury
patients undergoing surgery
Level
References
Foot pump plus
LMWH after
five days
In one RCT of trauma surgery patients, the use of a foot pump for five days
with the addition of LMWH at day five, significantly reduced DVT and occlusive
DVT. There was no difference in PE, wound or bleeding complications with this
regimen (compared with the use LMWH alone).
I
267
IPC (thigh, calf or
foot), warfarin or
foot pump.
There were a number of RCTs comparing a range of mechanical methods of
VTE prophylaxis with other mechanical or pharmacological methods in trauma
or spinal surgery patients. All of these were inconclusive or underpowered.
I
268-272
Discussion about the evidence and basis for recommendations for patients undergoing surgery for
trauma or spinal cord injury
Patients with major trauma are at high risk of VTE and those with spinal cord injury are at even
higher risk of VTE following trauma. Therefore thromboprophylaxis is recommended for all
trauma or spinal injury patients undergoing surgery.
Recommendation
Grade
1. Use thromboprophylaxis for all patients admitted to hospital for trauma surgery or spinal surgery.
GPP
RCTs comparing a range of mechanical methods of VTE prophylaxis with other mechanical
or pharmacological methods in trauma or spinal surgery patients were all inconclusive or
underpowered so no recommendations could be formulated from these.268-272 There was only
one RCT that provided conclusive evidence of thromboprophylactic benefit in trauma surgery
patients.267 This trial demonstrated that foot pump initiated at time of admission with the addition
of low molecular weight heparin five days after admission significantly reduced DVT and occlusive
DVT in trauma patients undergoing surgery.
Recommendation
Grade
2. In the absence of contraindications, use a foot pump from hospital admission with the addition of low
molecular weight heparin five days after admission for trauma patients undergoing surgery.
C
45
6.2 Anaesthesia
of VTE in patients who will be anaesthetised. Full evidence tables on which these summaries are
based are provided in Appendix D (table 148-149).
in section 3.
Evidence summary – thromboprophylaxis in anaesthetised patients
Regional
anaesthesia
(central neural
blockade)
In one systematic review of 11 studies273 and a further four RCTs, there were
significantly lower rates of DVT in patients receiving regional anaesthesia
compared with general anaesthesia (whether regional anaesthesia was epidural
or spinal).
Level
References
I
273-277
I
278,279
In seven of the RCTs, there were significantly lower rates of PE in patients
receiving regional anaesthesia compared with general anaesthesia (whether
regional anaesthesia was epidural or spinal).
There was no significant difference in major bleeding between patients
receiving regional and general anaesthesia in seven of the RCTs. Many RCTs
reported no bleeding events in either group.
Note: This evidence was for certain surgical procedures only (orthopaedic,
general or urological surgery including prostatectomy). Refer to anaesthesia
evidence tables for further details. (Appendix D 148-149)
Regional (central
neural blockade)
plus general
anaesthesia
In two RCTs there was no significant difference in rates of DVT between
patients receiving regional plus general anaesthesia compared with general
anaesthesia. There was significantly lower blood loss in patients receiving
regional plus general anaesthesia compared with general in on RCT.278
Discussion about the evidence and basis for recommendations for anaesthetised patients
RCTs demonstrated that patients receiving regional anaesthesia (also referred to as central
neural blockade), have significantly lower rates of DVT compared with those receiving general
anaesthesia.273-277 Therefore, it is recommended that whenever feasible, applicable and possible,
central neural blockade should be considered as an alternative to general anaesthesia (in line with
patient preference).
There is an increased risk of bleeding complications including both spontaneous bleeding at varied sites
as well as increased perioperative blood loss in patient’s receiving pharmacological thromboprophylaxis
and presenting for surgery.280 When a central neuraxial blockade is performed in an anticoagulated
patient, there is a risk of developing an epidural haematoma and the consequences of this can be
severe.44 Therefore, it is recommended that if central neural blockade is used, timing of pharmacological
prophylaxis should be carefully planned to minimise the risk of developing an epidural haematoma.
Where pharmacological prophylaxis is planned, the timing of such prophylaxis should be discussed
in advance with the anaesthetist, so that the possibility of using local anaesthesia by central
neural blockade is not compromised (where this form of anaesthesia is the most appropriate for
the patient).44
Recommendation
Grade
1. Consider central neural blockade as an alternative to general anaesthesia if feasible.
If central neural blockade is used, there is a risk of developing an epidural haematoma. To minimise this risk,
timing of pharmacological thromboprophylaxis should be carefully planned and discussed in advance with
the anaesthetist.
A
GPP
47
6.3Medical patients – Evidence and recommendations for
VTE prophylaxis
6.3.1 Stroke
of VTE in hospitalised stroke patients. Full evidence tables on which these summaries are based are
provided in Appendix D (table 131-138).
A stroke occurs when the supply of blood to the brain is disrupted. Stroke can be classified into
two major categories: ischaemic or haemorrhagic. Ischaemic stroke results from an interruption
to blood supply whilst haemorrhagic stroke is due to rupture of a blood vessel or an abnormal
vascular structure. Ischaemic stroke can result from an artery becoming blocked by a thrombosis
or an embolism.
in section 3.
VTE
prophylactic
agent
LMWH
Evidence summary relating to stroke patients in acute care
Across eight of nine RCTs, stroke patients* receiving LMWH had
significantly lower rates of PE when compared with those not receiving
any prophylaxis.
Level
References
I
281-286,288,289
In seven of the RCTs, there was no significant difference in intracranial
haemorrhage in patients receiving LMWH compared with no
treatment.
283-289
In six of the RCTs, there was no significant difference in extracranial
haemorrhage in patients receiving LMWH compared with no
treatment.
281,283-287
*The defined stroke patient populations across the trials included:
• stroke281-283
• acute ischaemic stroke284-286
• acute stroke287
• non-embolic ischaemic stroke288
• ischaemic stroke.289
In a systematic review of five RCTs, there was significantly lower
incidence of DVT with LMWH compared with UFH following
acute ischaemic stroke with no significant difference in intracranial
haemorrhage between the two groups. In three of the five RCTs,
there was no significant difference in extracranial haemorrhage
between LMWH and UFH.
I
290
VTE
prophylactic
agent
Evidence summary relating to stroke patients in acute care
Level
References
Danaparoid
or UFH
Danaparoid or UFH significantly reduced DVT rates in acute stroke
patients compared with no treatment.
I
291-297
298
However, there was significantly more extracranial haemorrhage in
one UFH RCT which used high doses of UFH (12500IU) compared
with no treatment.
296,297
There was also significantly more extracranial haemorrhage with
danaparoid compared with no treatment.
In a systematic review of pooled data from four RCTs, danaparoid was
more effective in reducing DVT in acute ischaemic stroke patients than
UFH. There was no significant difference in intracranial or extracranial
haemorrhage between danaparoid and UFH.
I
290
GCS
There was no difference in DVT in patients wearing graduated
compression stockings for seven days following acute stroke compared
with no treatment. There were no adverse effects with use of
graduated compression stockings.
I
299
IPC
One RCT comparing IPC with no treatment in acute stroke patients
was inconclusive.
I
300
Most acute ischaemic strokes take place when a blood clot blocks a blood vessel leading to the brain.
Anticoagulation may improve outcomes in ischaemic stroke patients where bleeding risk is low.37
Thromboprophylaxis should be considered in acute ischemic stroke patients, taking into account the
patient’s degree of immobility and their risk of bleeding. Thromboprophylaxis is not recommended in
haemorrhagic stroke patients due to the risk and consequences of intracranial bleeding.
Recommendation
Grade
1. Consider the use of thromboprophylaxis for all patients admitted to hospital with ischaemic stroke based on
an assessment of the patient’s degree of immobility and risk of bleeding.
B
Recommendation
Grade
2. Pharmacological thromboprophylaxis is not recommended for haemorrhagic stroke patients due to the risk
of intracranial bleeding.
GPP
Low molecular weight heparin, unfractionated heparin and danaparoid are all effective
VTE prophylactic agents following acute ischaemic stroke. Unfractionated heparin291-295 or
danaparoid296,297 significantly reduced DVT following acute ischaemic stroke. Whilst low molecular
weight heparin did not significantly reduce the rate of DVT across six RCTs, but did significantly
reduce the rate of PE compared with no treatment.281-286,288,289 Therefore, low molecular weight
heparin has been recommended in preference to unfractionated heparin for thromboprophylaxis
following acute ischaemic stroke.
49
Recommendation
Grade
3. Where thromboprophylaxis is appropriate and not contraindicated, use low molecular weight heparin for
patients with ischaemic stroke.
If low molecular weight heparin is contraindicated or not available, use unfractionated heparin.
B
B
6.3.2 Myocardial infarction (MI)
of VTE in medical patients hospitalised for myocardial infarction. Full evidence tables on which
these summaries are based are provided in Appendix D (table 139 and 140).
in section 3.
VTE
prophylactic
agent
Evidence summary – thromboprophylaxis for myocardial infarction patients Level References
UFH
Across six RCTs of MI patients where full anticoagulation was not employed post MI,
UFH significantly reduced rates of DVT and PE compared with no treatment. There
was no difference in adverse events such as bleeding or death.
I
301-306
LMWH
There was one RCT which compared LMWH and UFH in acute MI patients,
however this evidence was not relevant as treatment doses were used and the trial
did not report the outcomes of interest (other than mortality).
I
307
Discussion about the evidence and basis for recommendations for hospitalised patients following
myocardial infarction
Patients admitted to hospital following myocardial infarction (MI) are at increased risk of VTE.32
There were only a small number of studies examining thromboprophylaxis in patients with
myocardial infarction, most of which were more than 30 years old. Pooling of data from these
studies demonstrated that unfractionated heparin significantly reduced the rates of DVT and PE
following MI and did not increase the rate of bleeding (although there was no effect on proximal
DVT or death). One small RCT of 39 patients compared the effect on mortality of low molecular
weight heparin or unfractionated heparin; this study was excluded as it did not report any
outcomes other than mortality and treatment rather than prophylactic doses were used.307
In current practice, many patients are fully anticoagulated following myocardial infarction, and
therefore will not require further thromboprophylaxis. Where full anticoagulation is not employed
post myocardial infarction, thromboprophylaxis with unfractionated heparin is recommended.
Recommendation
Grade
1. Use thromboprophylaxis for patients admitted to hospital for myocardial infarction, where full anticoagulation
is not in use.
C
2. In the absence of contraindications, use unfractionated heparin for thromboprophylaxis following myocardial
infarction.
C
6.3.3General medical
of VTE in medical patients admitted to hospital. Full evidence tables on which these summaries are
based are provided in Appendix D (table 144 and 147).
No recommendations were made where the evidence was of poor quality or not relevant to the current
Australian healthcare context. Difficulties in interpreting the evidence are summarised in section 3.
VTE
prophylactic
agent
Evidence summary relating to general medical patients
LMWH
Across six RCTs of LMWH compared with no treatment for medical patients, those
who received LMWH experienced significantly lower rates of symptomatic PE
compared with those receiving no treatment. There was no significant difference
in major bleeding or death across the six trials.
Level
References
I
308-313
Patients with the following conditions or characteristics were included in these studies:
• congestive heart failure308-311
• acute or chronic respiratory failure308-311
• acute decompensated chronic obstructive pulmonary disease with mechanical
ventilation312
• acute infectious or rheumatologic disease308,310
• non-pulmonary sepsis309
• cancer309
• age over 40,309,310,312 over 60,312,313 or over 65.312
In three trials, patients receiving LMWH had significantly lower rates of proximal
DVT when compared with no treatment.
In three trials, there was no significant difference in fatal PE.
308,310,312
309-311
51
VTE
prophylactic
agent
Evidence summary relating to general medical patients
UFH
Across four RCTs of medical patients there was no difference in the rate of DVT
for patients receiving UFH compared with no treatment. However, when one study
which used autopsy to diagnose DVT in patients with infection was excluded,314
there were significantly lower rates of DVT in medical patients who received UFH
compared with no treatment.
Level
References
I
314,315,
319,320
I
321-325
I
326
• heart failure315,316
• chest infection315
• complete bed rest316
• obesity316
• previous vte316
• cancer316
• recent surgery316
• infection314
• critical care317
• age over 40316,318 or 55.314
Pooled data from two RCTs showed that UFH significantly reduced rates of PE. 314,315
In the one study which reported the rates of serious fatal bleeding or death, there
was no difference for patients receiving UFH compared with no treatment.314
LMWH
or UFH
Pooled data from five RCTs of medical patients showed that LMWH and UFH
conferred similar thromboprophylactic benefits and there was no significant
difference in adverse events.
• severe respiratory disease321
• heart failure321
• age over 18,321,322 40,323 50324 or 65.325
Fondaparinux
From one RCT of medical patients greater than 60 years of age, fondaparinux
appeared to reduce asymptomatic distal DVT, but did not reduce symptomatic DVT
or PE. There was no difference in deaths or major bleeding between fondaparinux
and no treatment.
Discussion about the evidence and basis for recommendations for general medical patients
Many medical patients admitted to hospital will be at increased risk of VTE due to individual
patient risk factors, or risks related to an acute medical illness. These are detailed in section 4,
Patient Risk. Therefore, individual assessment of the VTE risk is recommended for each patient.
Pooled data from six randomised controlled trials of low molecular weight heparin in a group of
mixed medical patients found that the rate of symptomatic PE was significantly lower for patients
receiving low molecular weight heparin compared with no treatment. These studies included a
range of medical conditions and patient groups, including congestive heart failure (three studies),
acute or chronic respiratory disease (three studies), and acute infectious or rheumatologic
disease (three studies). Pooled data from the three studies which reported the rate of fatal PE
found no difference between groups. Across three studies, there was a lower rate of proximal
DVT in patients treated with low molecular weight heparin; one of these studies was in patients
with acute decompensated chronic obstructive pulmonary disease, while the other two were in
patients with a range of conditions including congestive heart failure, acute or chronic respiratory
disease and acute infectious or rheumatologic disease. Therefore, low molecular weight heparin is
recommended for thromboprophylaxis in medical patients at risk of VTE.
Four studies compared medical patients who received unfractionated heparin with no treatment.
These studies included patients with a range of VTE risk factors (including immobility, increasing
age and obesity) and conditions which carry increased VTE risk (including heart failure). When
data from all of these studies were pooled, there was no difference between groups in the rate
of DVT. One study of patients with infection used autopsy to assess DVT, and found significantly
different results from the other three studies.314 When this study was excluded from the analyses,
the rate of DVT in patients receiving unfractionated heparin was significantly lower than the no
treatment group. There were no differences for death and bleeding (either bleeding complications
or serious fatal bleeding) between groups. Therefore, unfractionated heparin is recommended for
use in medical patients at risk of VTE.
Five studies compared medical patients receiving low molecular weight heparin with those
receiving unfractionated heparin.321-325 These studies included patients with congestive heart failure
and respiratory disease (other conditions were not listed). When data from these studies were
pooled, there was no difference between the rates of DVT, proximal DVT, PE, bleeding (major or
minor) or death. Therefore, either low molecular weight heparin or unfractionated heparin may be
used, depending on availability, cost and individual patients’ risk characteristics and preferences.
One study compared fondaparinux with no treatment for the prevention of VTE in medical patients
aged over 60.326 Compared with the no treatment group, patients receiving fondaparinux were less
like to develop an asymptomatic distal DVT; however there was no difference for asymptomatic
proximal DVTs, fatal PE, death, or major bleeding. No symptomatic DVTs were reported in either
group. The evidence from this trial was not sufficient to make a recommendation about the use of
fondaparinux in medical patients.
All of the evidence identified for prevention of VTE in general medical patients admitted to hospital
for this Guideline concerned pharmacological thromboprophylaxis. No randomised controlled trials
for mechanical methods of thromboprophylaxis were identified; therefore no recommendations
have been made for the use of mechanical thromboprophylaxis for this group of patients.
Recommendation
Grade
1. Consider the use of thromboprophylaxis for patients admitted to hospital for medical conditions based on an
assessment of the patient’s risk of VTE and bleeding.
2. In the absence of contraindications, use one of the following:
GPP
B
53
6.4Cancer patients – Evidence and recommendations for
VTE prophylaxis
Little evidence was available on VTE prevention in cancer patients admitted to hospital. Many of
the studies considered for the other surgical and medical sections of this Guideline included cancer
patients; however, sub-group analyses of the cancer patients in these studies were not feasible.
As a result, this section contains a narrative summary of evidence relevant to cancer patients, and
the related recommendations. For more information, refer to the specific section of the Guideline
(e.g. Abdominal surgery). All of the recommendations in this section are based on consensus, and
graded as Good Practice Points (GPP).
Discussion about the evidence and basis for recommendations for cancer patients admitted
to hospital
Epidemiological26,30,327,328 and hospital-based studies329 indicate that cancer confers an approximately
four-fold increased risk of thrombosis compared with age- and sex-matched control groups. Hormone
therapy has been linked with increased risk of thrombosis, and the newer targeted anti-cancer agents,
such as anti-angiogenic and cytokine therapies, are particularly implicated. Epidemiologic data shows
that the risk of thrombosis increases to six-fold for cancer patients undergoing chemotherapy.30,327
As the majority of cancer patients are elderly, and as the incidence of VTE increases dramatically in
patients aged greater than 55 years26, most if not all cancer patients admitted to hospital will fall into
a high risk group for subsequent VTE. The incidence of VTE in cancer patients undergoing surgery is
approximately twice that of patients without cancer undergoing comparable surgery.330
In general, the survival of cancer patients who develop VTE is worse than that of those who do not
develop VTE. Patients with cancer who have had a previous VTE have approximately two to three
times the rate of recurrence compared to patients without cancer.331,332
The impact of surgery on thrombosis risk depends upon the site of malignancy and type of surgery.
The risk is highest for those cancer patients undergoing major abdominal or pelvic surgery. Cancer
patients undergoing gynaecological surgery are also at high-risk.
Furthermore, there is generally a high incidence of late thrombosis in surgical cancer patients, with
up to 40 percent VTE events occurring more than 21 days after surgery, based on data from the
@RISTOS Study Group.333
Abdominal surgery: Studies of cancer patients165,334 and of surgery including cancer patients have
shown similar efficacy for both low molecular weight heparin and unfractionated heparin with no
differences in the incidence of side-effects such as haemorrhage, haematoma formation or need for
transfusion.335 Further studies suggest that four weeks of postoperative prophylaxis further reduces
VTE events.336,337
Neurosurgery: Neither low molecular weight heparin nor unfractionated heparin is associated with
serious haemorrhage and are more effective in preventing VTE than mechanical prophylaxis alone.338
In particular patients with glioma have a high incidence of delayed VTE, but extended prophylaxis
post-discharge has been associated with an increased risk of bleeding and is not recommended.
Head and neck cancer: These patients form a special group because of the complex nature
of associated reconstructive and microvascular surgery to support grafts where the patency of
the blood vessels to the graft is of paramount importance. Despite this, and the fact that they
have a higher risk of VTE compared to those patients undergoing non-malignant maxillo-facial
surgery, they remain at a relatively low risk of VTE. However, other risk factors for VTE should be
considered in making any decision regarding the provision of thromboprophylaxis.
Non-surgical cancer patients: Although there are no large RCTs specifically addressing
thromboprophylaxis in non-surgical cancer patients, both RCTs and observational studies have
shown a 50 to 70 percent reduction in VTE in medical in-patients receiving prophylaxis with low
molecular weight heparin.308,339 Sub-group analysis of a cohort of cancer patients (118 out of a
total of 1102) within the MEDENOX study of acutely ill medical patients showed a halving in VTE
occurrence (from 19.5 percent to 9.7 percent) although this did not reach statistical significance
because of the relatively small numbers.340
Recommendation
Grade
1. Use thromboprophylaxis for all cancer patients undergoing general surgical procedures including abdominal
or pelvic surgery or neurosurgery, provided there are no contraindications*.
GPP
Commence pharmacological thromboprophylaxis postoperatively and continue for at least seven to 10 days
following major general surgery for cancer. Use one of the following:
2. Consider using extended thromoprophylaxis with low molecular weight heparin for up to 28 days after
major abdominal or pelvic surgery for cancer, especially in patients who are obese, slow to mobilise or have a
past history of VTE.
GPP
3. In the absence of other significant risk factors, thromboprophylaxis is not recommended for cancer patients
undergoing head and neck surgery.
GPP
4. In non-surgical cancer patients in the absence of contraindications, commence thromboprophylaxis on
admission and continue until discharge. Use one of the following:
GPP
5. For both non-surgical and surgical cancer patients, use graduated compression stockings if pharmacological
thromboprophylaxis is contraindicated.
GPP
*In patients with the following characteristics, pharmacological prophylaxis is contraindicated:341
•recent central nervous system bleeding
•intracranial or spinal lesion at high risk for bleeding
•current active major bleeding, defined as requiring at least two units of blood or blood products
to be transfused in 24 hours
•current chronic, clinically significant and measurable bleeding over 48 hours
•thrombocytopenia (platelets < 50,000/µl)
•severe platelet dysfunction (due, for example to uraemia, medications, or myelodysplasia)
•recent major surgical procedure at high risk for bleeding
•underlying coagulopathy or coagulation factor abnormalities
•regional axial anaesthesia or recent lumbar puncture for any reason
•high risk of falls.
55
6.5 Pregnancy and childbirth – Evidence and recommendations for
VTE prophylaxis
There is a lack of high level formal evidence to guide recommendations regarding prevention of
VTE in pregnancy and the early postnatal period for women admitted to hospital.342 As a result, this
section contains a narrative summary of the available evidence for thromboprophylaxis relevant to
pregnancy and the early postnatal period, and related recommendations based on consensus, and
graded as Good Practice Points (GPP).
Evidence and recommendations for pregnancy and childbirth in women admitted to hospital
VTE during pregnancy and the immediate postnatal period is rare, but when it occurs, it is
associated with high degrees of morbidity and mortality.343 For example the ratio of major proximal
thrombosis (ilio-femoral) to below knee DVT is much higher in pregnancy, and pulmonary
embolism is amongst the three most common causes of death in pregnancy.344 A Cochrane
review identified the best estimate of incidence as 0.13 percent.342 Other estimates varying from
0.06 percent345 to 0.11 percent346 have been published.
Pregnancy is a risk factor for VTE, with up to a ten-fold increase in risk in comparison with
non-pregnant women.347,348 The risk is even higher if delivery is by caesarean section, especially
emergency caesarean section.349 Women who have had a previous VTE have an increased risk
of recurrence during pregnancy. A retrospective comparison of the overall risk of VTE recurrence
in women with a previous VTE revealed risks of 3.7 percent per year outside pregnancy and
10.9 percent during pregnancy and the post-partum period.350
PE is the most common direct cause of maternal death in the UK.351 Although most VTE occurs
antenatally, the risk per day is greatest in the six weeks immediately after delivery.352
Recommendation
Grade
1. Minimise immobilisation of women during pregnancy, labour and the puerperium and ensure adequate
hydration at all times.
GPP
2. All women who deliver by caesarean section are at increased risk of VTE and should be mobilised promptly
after surgery.
GPP
Thromboprophylaxis with low molecular weight heparin has been proven effective in many
postoperative settings and has been adopted for use in the period after caesarean. Both low
molecular weight heparin and warfarin are safe for women who are breast feeding.23 Low
molecular weight heparin has been shown to be associated with abnormal bleeding less often than
unfractionated heparin342 although both are associated with bleeding in some cases. Low molecular
weight heparin in prophylactic dose is recommended for at least five to seven days after caesarean
(and longer if return to full mobility is delayed) for women who have additional risk factors.353
The first dose should be administered no less than four hours after surgery, with due attention to
guidelines relating to the removal of epidural or spinal cannulae.
Note: When used after caesarean section, low molecular weight heparin may increase the
frequency of bleeding and wound haematoma. Anticoagulation is contraindicated in women
with primary postpartum haemorrhage >1000mls. Pharmacological prophylaxis is not recommended
in these women but may be used in high risk cases when haemostasis is considered secure by
the obstetrician.
Timing
Postpartum thromboprophylaxis should be given as soon as possible after delivery by caesarean
section, provided that there is no postpartum haemorrhage.
Those with postpartum haemorrhage should be fitted with graduated compression stockings.
If the woman has been given regional analgesia, low molecular weight heparin should be withheld
until four hours after insertion or removal of the epidural catheter (or six hours if either insertion or
removal were traumatic). The first postpartum dose can be given after insertion but before removal
of the epidural catheter.
Given the absence of evidence about mechanical methods, it was not possible to make a graded
recommendation about their use. However, these have been shown to be beneficial in many
other clinical categories, and therefore should be considered for women admitted to hospital
during pregnancy and continuing into the early postnatal period.
Recommendation
Grade
3. Where pharmacological thromboprophylaxis is appropriate and not contraindicated, use low molecular
weight heparin after caesarean delivery for five to seven days, or until the patient is fully mobile.
GPP
4. Extend pharmacological thromboprophylaxis with low molecular weight heparin or adjusted dose warfarin
to six weeks for high risk women, after caesarean or vaginal delivery.
GPP
5. Consider the use of graduated compression stockings if pharmacological thromboprophylaxis is
contraindicated or not used.
GPP
6. Consider the use of intermittent pneumatic compression during caesarean and in the postoperative period
for up to 24 hours.
GPP
57
7 Areas for future research
The development of this Guideline has highlighted gaps which suggest areas for future research,
including: knowledge relating to the prevalence of known risk factors for VTE and the magnitude
of risk, and evidence on the effectiveness of VTE prevention in specific situations.
7.1 Risk of VTE
More information is required on the risk of VTE for patients undergoing certain surgical
procedures, including laparoscopy, bariatric surgery, plastic and reconstructive surgery, and minor
gynaecological surgery (especially in the presence of other risk factors). There are information gaps
in risk stratification for urological surgery and lower limb injuries.
Evidence-based algorithms for risk assessment do not currently exist, and the evidence about
combining risk factors is sparse.
7.2Effectiveness of thromboprophylactic agents
There are significant gaps in the evidence for some thromboprophylactic agents and regimens for
specific conditions. These include:
•the effectiveness of GCS in medical patients
•the effectiveness of oral anticoagulants in medical patients
•the use of mechanical devices, including duration of use, acceptability, adherence to
recommended regimens, and techniques of application
•the effectiveness of sequential prophylaxis, e.g. in general surgery or gynaecological surgery
•the appropriateness of vena caval filters in trauma patients
•the comparative effectiveness of thigh versus knee length graduated compression stockings
•the longer-term side-effects of dabigatran etexilate and rivaroxaban.
7.3 Areas with little evidence for thromboprophylaxis
A number of patient groups with specific conditions or undergoing specific procedures are known
to be at increased risk of VTE, but there is little or no evidence on effective thromboprophylaxis in
these patients. These include:
•medical patients
•patients undergoing curative surgery for cancer
•cancer patients not undergoing surgery
•patients undergoing major head and neck surgery (including cancer patients)
•pregnant women
•obese patients.
7.4 Other issues
The following issues also warrant consideration for research:
•the detection of VTE
•the relationship between asymptomatic and symptomatic DVT
•an agreed definition of ‘major bleeding’
•the incidence of epidural haematoma (with or without neuraxial regional anaesthesia)
when thromboprophylaxis is used.
59
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336.Bergqvist D, Agnelli G, Cohen AT, et al. Duration of prophylaxis against venous
thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002;346(13):975-80.
337.Rasmussen M, Jorgensen L, Wille-Jørgensen P, et al. Prolonged prophylaxis with dalteparin to
prevent late thromboembolic complications in patients undergoing major abdominal surgery:
a multicenter randomized open-label study. J Thromb Haemost 2006;4(11):2384-90.
338.Carrier M, Lee AY. Prophylactic and therapeutic anticoagulation for thrombosis: major issues
in oncology. Nat Clin Pract Oncol 2009;6(2):74-84.
339.McGarry LJ, Thompson D. Retrospective database analysis of the prevention of venous
thromboembolism with low-molecular-weight heparin in acutely III medical inpatients in
community practice. Clin Ther 2004;26(3):419-30.
340.Alikhan R, Cohen AT, Combe S, et al. Prevention of venous thromboembolism in medical
patients with enoxaparin: a subgroup analysis of the MEDENOX study. Blood Coagul
Fibrinolysis 2003;14(4):341-6.
341.National Comprehensive Cancer Network Guidelines. Venous Thromboembolic Disease
Clinical Practice Guidelines in Oncology. 2008.
342.Gates S, Brocklehurst P, Davis LJ. Prophylaxis for venous thromboembolic disease in
pregnancy and the early postnatal period. Cochrane Database Syst Rev 2002(2):CD001689.
343.Royal Women’s Hospital. Thromboprophylaxis in women undergoing caesarean section,
Guideline. 2006.
344.Sullivan EA, Hall B, King JF. Maternal deaths in Australia 2003-2005. Maternal deaths series no. 3.
Sydney: AIHW Perinatal Statistics Unit, 2007: 51.
345.Gherman RB, Goodwin TM, Leung B, Byrne JD, Hethumumi R, Montoro M. Incidence,
clinical characteristics, and timing of objectively diagnosed venous thromboembolism during
pregnancy. Obstet Gynecol 1999;94(5 Pt 1):730-4.
346.Macklon NS, Greer IA. Venous thromboembolic disease in obstetrics and gynaecology: the
Scottish experience. Scott Med J 1996;41(3):83-6.
347.McColl MD, Ramsay JE, Tait RC, et al. Risk factors for pregnancy associated venous
thromboembolism. Thromb Haemost 1997;78(4):1183-8.
348.Simpson EL, Lawrenson RA, Nightingale AL, Farmer RD. Venous thromboembolism in
pregnancy and the puerperium: incidence and additional risk factors from a London perinatal
database. Bjog 2001;108(1):56-60.
349.Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy:
the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126
(3 Suppl):627S-644S.
350.Pabinger I, Grafenhofer H, Kyrle PA, et al. Temporary increase in the risk for recurrence during
pregnancy in women with a history of venous thromboembolism. Blood 2002;100(3):1060-2.
351.Drife J, Lewis G. Why Mothers Die 1997-1999: Fifth Report of the Confidential Enquiries into
Maternal Deaths in the United Kingdom. In: Drife J, Lewis G, eds. London: Royal College of
Obstetricians and Gynaecologists, 2001.
352.Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis
of the period of risk and the leg of presentation. Obstet Gynecol Surv 1999;54(4):265-71.
353.Royal College of Obstetricians and Gynaecologists. Thromboprophylaxis during pregnancy,
labour and after vaginal delivery, Guideline No. 37. 2004.
354.Nicolaides A, Fareed J, Kakkar A, et al. Prevention and treatment of venous thromboembolism –
International Consensus Statement (Guidelines according to scientific evidence) Int Angiol
2006;25(2):101-161.
355.Institute for Clinical Systems Improvement. Venous Thromboembolism Prophylaxis. 2007.
356.Khorana A. The NCCN Clinical Practice Guidelines on Venous Thromboembolic Disease:
strategies for improving VTE prophylaxis in hospitalized cancer patients. 2007.
357.Lyman G, Khorana A, Falanga A, et al. American Society of Clinical Oncology Guideline:
Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients
With Cancer. Journal Of Clinical Oncology 2007;25(34).
358.Stahl T, Gregorcyk S, Hyman N, Buie W, Surgeons. SPTFoTASoCaR. Practice parameters for
the prevention of venous thromboembolism. Dis Colon Rectum. 2006;49(10):1477-83.
359.The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Guidelines for
Deep Venous Thrombosis Prophlaxis During Laparoscopic Surgery. 2006.
360.Clinical Issues Committee of the American Society for Metabolic and Bariatric Surgery.
Prophylactic measures to reduce the risk of venous thromboembolism in bariatric surgery
patients. Surg Obes Relat Dis. 2007;3(5):494-495.
361.Gaber T. Guidelines for prevention of venous thromboembolism in immobile patients
secondary to neurological impairment. Disabil Rehabil. 2007;15(29(19)):1544-1549.
362.Rogers F, Cipolle M, Velmahos G, Rozycki G, FA. L. Practice management guidelines for the
prevention of venous thromboembolism in trauma patients: the EAST practice management
guidelines work group. J Trauma. 2002;53(1):142-164.
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363.Palumbo Aea. Prevention of thalidomide – and lenalidomide-associated thrombosis in
myeloma. 2008.
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parameters for the prevention of venous thromboembolism. The Standards Task Force of the
American Society of Colon and Rectal Surgeons. Dis Colon Rectum. 2000;43(8):1037-1047.
365.American Geriatrics Society. The use of oral anticoagulants (warfarin) in older people.
American Geriatrics Society guideline. 2002.
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bulletin. 2001.
367.Gallus A, Baker R, Chong B, Ockelford P, AM. S. Consensus guidelines for warfarin therapy.
Recommendations from the Australasian Society of Thrombosis and Haemostasis. 2000.
368.Faucher L, Conlon K. Practice Guidelines for deep vein prophylaxis in burns. 2007.
9 Appendices
Appendix A: VTE Prevention Guideline Adaptation Committee
A.1
Membership of the VTE Prevention Guideline Adaptation Committee
Members
Expertise
Details
Chair
Clinical
Epidemiologist
Adjunct Professor, School of Public Health, The University of Sydney
Director – Sydney Health Projects Group
Prof A.B. Baker (Barry)
Anaesthetist
Emeritus Professor, The University of Sydney
Director Professional Affairs, Australian and New Zealand College of Anaesthetists
Nominee of the Australian and New Zealand College of Anaesthetists
Ms Kay Currie
Guidelines
Research
Director, Guidelines Research Program
National Institute of Clinical Studies (NICS)
Prof John Fletcher
Vascular
Surgeon
Professor of Surgery, The University of Sydney
Westmead Hospital, Sydney
Rep of the Australia and New Zealand Working Party on the Management and
Prevention of Venous Thromboembolism (Chairman)
Prof Alex Gallus
Physician/
Pathologist
Professor of Haematology, Flinders University and Director of Pathology Services
at Flinders Medical Centre, SA
Rep of the Australia and New Zealand Working Party on the Management and
Prevention of Venous Thromboembolism (Member)
Ms Sharon
Goldsworthy
Pharmacist
Clinical Pharmacy Team Leader
The Queen Elizabeth Hospital & Health Service, Woodville South, SA
Nominee of the Society for Hospital Pharmacists Australia
Ms Christine Griffiths
Patient
Representative
Nominee of Health Issues Centre
Ms Jeannette Kamar
Nurse
Injury Prevention
The Northern Hospital, Epping
Nominee of the Royal College of Nursing, Australia
Ms Philippa Middleton
Methodologist
Research Leader with the Australian Research Centre for Health of Women
and Babies (ARCH) in the Discipline of Obstetrics and Gynaecology
The University of Adelaide, SA
Contracted Methodologist
Dr Sue Phillips
Research
Implementation
Director, Research Implementation Program
* Dr Sue Phillips has been represented by Ms Sonja Hood since August 2008
Dr Rebecca Tooher
Methodologist
Research Fellow with the Australian Research Centre for Health of Women
and Babies (ARCH) in the Discipline of Obstetrics and Gynaecology
The University of Adelaide, SA
Contracted Methodologist
A/Prof Barry Walters
Obstetrics
Physician
Clinical Assoc Professor, Obstetrics and Internal Medicine
Royal Perth Hospital and King Edward Memorial Hospital for Women, Perth
Nominee of the Royal Australian and New Zealand College of Obstetrics
and Gynaecology
A/Prof Christopher
Ward
Physician
Department of Haematology Transfusion Medicine
Royal North Shore Hospital
Nominee of the Royal Australasian College of Physicians
A/Prof Nicholas
Wickham
Oncologist
Consultant Haematologist
Adelaide Cancer Centre
Nominee of the Medical Oncology Group of Australia
Mr Simon Williams
Orthopaedic
Surgeon
Orthopaedic Surgeon, VMO Geelong Hospital,
St John of God Hospital & Geelong Private Hospital
Nominee of the Royal Australasian College of Surgeons
Dr Agnes Wilson
VTE ADAPTE
Project Support
Research Scientist, Research Implementation Program
Prof Michael Frommer
81
A.2
Declarations of interest of the VTE Prevention Guideline Adaptation Committee
1. Professor Michael Frommer
• undertook a review of literature on VTE prevention and prepared a short report for the
NSW Health Department in 2000
• current member of the Pharmaceutical Benefits Advisory Committee and its Economic
Sub-committee.
2. Professor Barry Baker
• participated in the development and endorsement of a guideline for the use of surgical
prophylaxis for departmental use at the Department of Anaesthetics, Royal Prince Alfred
Hospital Sydney (North American published guidelines used as a source for the Royal Prince
Alfred guideline).
3. Professor Alex Gallus
• Member of an independent data safety monitoring board for a heparin-like synthetic
angiogenesis inhibitor
• Chair of the guideline development and publication committee of the Australasian Society of
Thrombosis and Haemostasis (guidelines for warfarin)
• Member of a guidelines committee which prepared OMGA guidelines for antithrombotics
in pregnancy
• Member of international steering committee for clinical trials in VTE prevention of an orally
active Factor Xa inhibitor under development by Bristol-Myers Squibb and an orally active
Factor Xa inhibitor under development by Astellas
• prior Member of a steering committee for two phase II venous thrombosis treatment trials
using rivaroxaban, the ODIXa trial, and the EINSTEIN trials
• Member of the steering committee overseeing the venous thromboembolism treatment trials
with rivaroxaban, the continuing phase III EINSTEIN trials (since January 2007)
• Member of a rivaroxaban expert advisory panel which offers advice to Bayer regarding
thrombosis prevention
• Member of the Australia and New Zealand Working Group for VTE Prevention and VTE
therapy guidelines group.
4. Ms Sharon Goldsworthy
• participated in maintenance of hospital based guidelines for VTE prevention in adult surgical
and medical patients
• participated in the roll-out of state-based, local guidelines for VTE prevention
(in South Australia)
• Member of a steering group for a VTE project nurse funded by Janssen-Cilag.
5. Professor John Fletcher
• Member of an advisory board for PharmaLink (for drugs not relevant to VTE)
• Prior member of the following advisory panels: Astra-Zeneca, Sanofi-Aventis and Pharmacia
• Current member of advisory board for Bayer
• In 2008, research funding was received by Westmead Hospital from Sanofi-Aventis for VTE
Nurse for six months
Professor John Fletcher (cont.)
• travel costs and honorarium received from Bayer for invited presentation on “VTE
prevention in orthopaedic surgery – an Australian perspective” at the Asia-Pacific Advisory
Board meeting of Bayer Schering Pharma, Hong Kong, August 24 2008 and travel costs to
attend the American Society of Hematology meeting, San Francisco 5-9 December 2008
• travel costs and honorarium from Glaxo Smith Kline for invited presentation on “Prevention
of VTE: current perspectives” at the 70th annual meeting of the Japanese Surgical
Association, Tokyo, 27-29 November 2008 and participation in a VTE expert panel meeting
• Advisor to Executive Board of International Union of Angiology (IUA), contributor to
“Consensus statement, Prevention of venous thromboembolism, Int Angiol 1997; 16:3-38”,
“Prevention of venous thromboembolism, International consensus statement, Guidelines
compiled in accordance with the scientific evidence, Int Angiol 2001; 20:1-37” and
“Prevention of venous thromboembolism, International consensus statement (Guidelines
according to scientific evidence), Int Angiol 2006; 25:101-161”
• Chairman of the Australia and New Zealand Working Group for VTE Prevention
• President, International Surgical Thrombosis Forum (ISTF) 2008.
6. Dr Sue Phillips
• employed by the NHMRC to lead the implementation of best practice guidelines in key
priority areas, including VTE.
7. A/Professor Barry Walters
• participated in the development of a VTE Prevention Guideline: King Edward Memorial
Hospital Obstetric Thromboembolism Guideline
• in 2008, received three months of funding for a research nurse from an organisation that has
a commercial interest in VTE prevention
• in 2008, participated in one meeting as a member of panel/committee for Sanofi-Aventis
(in a consultant capacity).
8. A/Professor Christopher Ward
• endorsed the 4th edition of “Best Practice Guidelines for the prevention of VTE” (Australia
and New Zealand Working Group for VTE Prevention) at the Royal North Shore Hospital
• previous member of advisory boards for Astra-Zeneca and Sanofi-Aventis regarding the
development of new anticoagulants
• current member of advisory boards for Amgen and Celgene (for development of drugs not
relevant to VTE prevention)
• principal investigator in clinical trials of new anti-coagulants (Sanofi-Aventis, Bristol-Myers
Squibb, Bayer, Pfizer)
• Department receives funding for performance of clinical trials as per CTA
• recipient of an unrestricted research grant from Pharmion
• received financial support to attend international trial meetings and scientific conferences
from Pharmacia, Pharmion, Amgen, Bristol-Myers Squibb, Bayer, Sanofi-Aventis, Celgene
and Pfizer
• received honoraria for advisory board/lectures from Amgen, Sanofi-Aventis and Celgene
• Member of a drug safety board for myeloma phase I trial (sponsored by Immune System
Therapeutics)
• delivered a presentation in a session at the 2008 Annual Clinical Oncological Society of
Australia conference which was sponsored by Sanofi-Aventis.
83
9. A/Professor Nicholas Wickham
• participated in the revision of “Anticoagulant Guidelines” for The Queen Elizabeth Hospital
North West Adelaide Health Service 1997 (for the Department of Haematology and
The Queen Elizabeth Hospital Drug Committee).
10. Mr Simon Williams
• Principal Investigator for Sanofi-Aventis trials of fondaparinux versus clexane in total hip
replacment (Pentathlon) and fractured neck of femurs (pentifra and pentifra plus) in 2000.
Research department received funding for this involvement. In 2000, received direct financial
assistance in attending meetings in Queensland and London based on Sanofi-Aventis trials.
• Member of the Geelong Hospital Orthopaedic Unit which was involved in the Glaxo-Smith
Kline trial (TOPVENT) in 2006 and the Bayer RECORD trial in 2007 which investigated oral
anticoagulation following total knee replacement. Funding towards research nurse received
from both companies. No direct financial funding received.
11. Dr Agnes Wilson
• employed by the NHMRC to produce the VTE prevention guideline.
The other members of the VTE Prevention Guideline Adaptation Committee did not report any
competing interests.
A.3Terms of reference of the VTE Prevention Guideline Adaptation Committee
Purpose
To produce an evidence-based, usable guideline for the prevention of venous thromboembolism in
adult surgical and medical patients admitted to Australian metropolitan, regional and rural hospital
settings through adaptation of suitable existing international guidelines.
The role of the VTE Prevention Guideline Adaptation Committee is to:
•determine the clinical questions to be addressed in the guideline
•identify and consider the evidence from suitable existing international guidelines
•translate the evidence into broad findings
•use a formal consensus process for decision making where there is disagreement
•identify health outcomes and outcome measures
•develop the recommendations
•formulate the guideline, including implementation plans and plans for review and update
•ensure that the guideline is a useful and implementable resource for clinicians, managers and
patients, and that the guideline is relevant to the Australian healthcare context.
Summary of the Adaptation Process
The VTE Prevention Guideline Adaptation Committee will adapt existing high quality international
VTE prevention guidelines using the ADAPTE methodology for guideline adaptation. A summary of
the steps in the process can be found in the figure on the next page1.
1
Manual for Guideline Adaptation. ADAPTE Collaboration Version 1.0. 2007
The ADAPTE Methodology
Finalisation phase
Adaptation phase
Set up phases
PHASES
TASKS
Prepare for ADAPTE process
ASSOCIATED MODULES
Preparation
Define health questions
Scope and
purpose
Search and screen guidelines
Search and
screen
Assess guidelines
Assessment
Decide and select
Decision
and
selection
Draft guideline report
Customisation
External
review
Aftercare
planning
Final
production
85
Membership of guideline adaptation committee
The VTE Prevention Guideline Adaptation Committee will ideally comprise 13–15 members.
Membership of guideline groups should be multi-disciplinary, comprising clinicians (both content
area specialists and generalists), patients and technical experts (methodologists and individuals
with expertise in guideline appraisal).
The VTE Prevention Guideline Adaptation Committee will ideally have members with expertise in:
•general surgery (or vascular specialist)
•orthopaedic surgery
•obstetrics and gynaecology
•haematology
•medicine (general, respiratory or cardiac medicine)
•nursing
•hospital pharmacy
•oncology
•anaesthesiology
•guideline appraisal methodology
•guideline implementation
•consumer experience.
Frequency of meetings
There will be approximately five meetings between June 2008 and June 2009. The guideline
adaptation committee will meet every six weeks for the first three meetings (early June to late
August 2008). There will be quarterly meetings thereafter until June 2009.
It is anticipated that the guideline adaptation committee will be a working committee and
their clinical expertise will be sought in determining the clinical questions and formulating
the recommendations.
Deliverables
By the projected project completion date of June 2009, it is expected that there will be an adapted
guideline suitable for use in Australian hospital settings.
The types of documents to be produced include a long version of the guideline, a short version
and a patient information guide. Implementation resources will also be considered.
Appendix B: Overview of the guideline development process
In early 2008, the NHMRC undertook to develop this Guideline for the “Prevention of venous
thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to
Australian hospitals”. This Guideline has been developed by the NHMRC’s National Institute of
Clinical Studies (NICS) in accordance with the NHMRC toolkit series,17-19 under the direction of a
multi-disciplinary guideline adaptation committee (refer to Appendix A).
At the commencement of the guideline development process, a search revealed that there were
a number of existing evidence-based international guidelines in VTE prevention (published
between 2002 and 2008).6,7,10,39,354,355 NICS opted to take a pragmatic approach to the development
of this VTE prevention guideline by choosing to adapt existing international VTE prevention
guidelines. A structured guideline adaptation methodology known as ADAPTE was employed for
development of this Guideline.20 ADAPTE is a methodology that provides a systematic approach
to aid in the adaptation of guidelines produced in one setting for use in a different cultural and/or
organisational context.
ADAPTE comprises three phases; set-up, adaptation and finalisation.20 A number of components of
guideline development were considered as part of the set-up phase of ADAPTE. These included
establishing:
•the scope of the guideline
•the process for dealing with conflicts of interest
•a consensus process for decision making
•the resources required for guideline adaptation (including time, cost and required expertise).
The set-up phase involved convening an organising committee to assist with consideration of
these components. As recommended by the ADAPTE methodology, an organising committee was
established and comprised:
•NICS staff who were working on development of the guideline (Dr Sue Phillips and
Dr Agnes Wilson)
•individuals with guideline development and methodological expertise (Ms Kay Currie and
Dr Heather Buchan)
•individuals with clinical expertise in VTE prevention (Professor John Fletcher and
Professor Alex Gallus).
It is important to note that this organising committee only considered matters related to the process
of guideline adaptation, they did not undertake any direct guideline development.
The organising committee convened for a day-long meeting in late April 2008. Disclosures of
interest were obtained from all organising committee members prior to their participation in this
committee. At this meeting, a draft scope for the guideline was formulated and the resources
required for guideline development were discussed. NICS staff developed the conflict of interest
policy and procedure and the consensus process for decision making independent of the
organising committee.
87
B.1Appointing the committee
Following the organising committee meeting, NICS established a multi-disciplinary VTE Prevention
Guideline Adaptation Committee in June 2008 to produce the guideline through adaptation.
The following professional organisations involved in the management of patients at risk of VTE
were invited to nominate a representative to become a member of the VTE Prevention Guideline
Adaptation Committee:
•The Royal Australasian College of Surgeons (RACS)
•The Royal Australasian College of Physicians (RACP)
•The Australian and New Zealand College of Anaesthetists (ANZCA)
•The Royal College of Nursing, Australia (RCNA)
•The Medical Oncology Group of Australia (MOGA)
•The Society of Hospital Pharmacists Australia (SHPA)
•The Royal Australian and New Zealand College of Obstetrics and Gynaecology (RANZCOG).
Each of these professional organisations is represented in the guideline adaptation committee by
one of its nominated members. Consumer groups were also invited to nominate representatives for
the guideline adaptation committee. Health Issues Centre nominated one patient representative for
this work. Two members from the Australia and New Zealand Working Party for the Prevention of
Venous Thromboembolism were also invited to become members of the VTE Prevention Guideline
Adaptation Committee. The ANZ Working Party had previously independently compiled a short
summary document on VTE prevention based on international guidelines.
The 16-member VTE Prevention Guideline Adaptation Committee was established from the
nominations received from the key stakeholder organisations (and included a project manager
and two contracted methodologists) (refer to Appendix A1). In total, eight day long, face-toface meetings were held over the duration of the guideline adaptation process to get to the draft
guideline stage.
B.2Declaration of interest process
Conflict of interest can be categorised as potential, perceived or actual and relate to members’
interests as well as the interests of their family relating to the guideline topic. Interests may be
direct or indirect, pecuniary or non-pecuniary. A process for dealing with conflict of interest was
developed by NICS and was in accordance with the NHMRC’s “Members’ Responsibilities regarding
Disclosure of Interest and Confidentiality” which applies to all members of the Council of the
NHMRC, Principal Committees and Working Committees (in accordance with the requirements
of the National Health and Medical Research Council Act 1992). In addition, members of this
committee were asked to declare specific interests related to guideline development (as advised in
the ADAPTE methodology). Where committee members were identified as having significant real
or perceived conflicts of interest, the Chair could request they step out of the room on matters they
were conflicted on. Alternatively, the Chair could decide that the member may stay in the room
but not participate in the discussion, or decision making on the specific area where they were
conflicted. The period of exclusion and the conflict to which it related to was recorded in
the meeting minutes.
The VTE Prevention Guideline Adaptation Committee members were required to declare their
relevant interests in writing prior to appointment to this committee (interests may have included:
consultancies, fee-paid work, share-holdings, fellowships and support from the healthcare
industry). The purpose of declaring conflicts of interest was to avoid any conflict between the
private interests of members and their duties as part of the committee (including pecuniary
interest or the possibility of other advantage). Committee members were required to update their
information as soon as they become aware of any changes to their interests. There was also a
standing agenda item at each meeting where declarations of interest were called for and these
were recorded as part of the meeting minutes.
All declarations of interest were added to a register of interests (Appendix A.2). This register was
seen by the NHMRC and NICS and was made available to the VTE Prevention Guideline Adaptation
Committee. The disclosure of the register of interest to all Committee members was important to
allow Committee members are able to take all potential conflicts of interest into consideration in
discussions, decision-making and formulation of recommendations.
B.3
Steps in the development of an NHMRC clinical practice guideline
The VTE Prevention Guideline Adaptation Committee undertook the following steps in developing
this Guideline (supported by the methodologists and NICS project staff):
1. Developed structured clinical questions.
2. Selected high-quality source documents to use for adaptation.
3. Developed a search strategy and searched the literature.
4. Assessed the eligibility of identified studies.
5. Critically appraised the included studies.
6. Summarised and where appropriate statistically pooled included studies.
7. Assessed the body of evidence and formulated recommendations.
The first Committee meeting in June 2008 was spent discussing and agreeing upon the scope and
target audience for this Guideline, and the clinical questions that this Guideline would address
were formulated.
B.3i
Developing structured clinical questions
The VTE Prevention Guideline Adaptation Committee formulated a list of clinical questions to be
addressed as part of this Guideline at their first meeting. The methodologists assisted the Committee
in structuring the questions according to a PICO formula (Populations, Intervention, Comparisons
and Outcomes). The full list of clinical questions that this Guideline hoped to address is provided
in Appendix C.
B.3ii
Selecting high quality source guidelines to use for adaptation
As there were a number of high quality international VTE prevention guidelines available, NICS
decide to use a guideline adaptation process to develop this Guideline. ADAPTE was employed as
the methodology for adaptation.20
Following the ADAPTE process, a number of international guideline databases were searched
for VTE prevention guidelines using the following terms: venous thromboembolism prophylaxis
AND adult population. This search revealed 36 VTE prevention guidelines. Of these, four were
excluded because they were not available in English and 13 guidelines were excluded as they
did not directly quote evidence or were an earlier version of a current guideline. Five of the VTE
prevention guidelines crossed disciplines and diseases6,9,10,39,355 and 14 were either discipline or
disease specific VTE prevention guidelines.104,356-368
NICS short-listed the five cross-discipline, cross-disease VTE guidelines as potential source
guidelines for adaptation. One of these guidelines was excluded as it was six years old and was
not considered current.10 The ADAPTE methodology advises that an assessment of the quality of
potential source guidelines should be undertaken using the AGREE instrument.21 The NICE and
89
American College of Chest Physicians (ACCP) VTE prevention guidelines both rated highly for the
quality of the development process of the guideline.6,39 However, the AGREE instrument does not
evaluate the content of guidelines, and it became apparent as the Committee considered these
two guidelines that neither would be entirely suitable for adaptation. The ACCP guidelines did not
contain evidence tables and were therefore more difficult to use as a direct source of evidence for
this Guideline. On the other hand, evidence tables were readily available from the NICE guideline,
making it suitable for adaptation, with cross-checking against the studies referred to in the ACCP
guidelines to ensure completeness.
The NICE guideline framed the clinical questions according to prophylaxis options rather than
clinical specialty. The Committee felt that this would not be as useful for clinicians for this
Guideline to be organised according to the indication for prophylaxis. It was therefore not possible
to adapt the recommendations from the NICE guidelines directly as suggested by the ADAPTE
process. Instead, the NICE guideline evidence tables were used as the primary source of evidence
with new meta-analysis and recommendations being developed.
NICS approached the lead authors of both the NICE and ACCP VTE prevention guidelines for
permission to adapt these guidelines to Australian circumstances. Permission was granted.
B.3iii Developing a search strategy and searching the literature
Literature searches undertaken for the 2007 NICE guideline “Venous thromboembolism: reducing
the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in
inpatients undergoing surgery” were used as a basis for the evidence, with top-up searches
undertaken (from April 2006 to January 2009) to ensure currency and completeness.39 As this
Guideline cover all hospitalised patients, a separate search for studies evaluating interventions
designed to reduce or prevent VTE in adult hospitalised patients not undergoing surgery was
conducted from inception of the databases until January 2009.
A broad search strategy was adopted for both medical and surgical studies, in order to retrieve
as many potential relevant citations as possible. This consisted of the MeSH terms (exploded):
venous thrombosis, venous thromboembolism, pulmonary embolism and the keywords: DVT, deep
vein thrombosis.
The Cochrane Library was searched for relevant Cochrane reviews, other systematic reviews and
RCTs (last searched Issue 1, 2009). PubMed was last searched on January 30, 2009. References of
retrieved articles were checked for potentially relevant studies.
B.3iv Assessing the eligibility of studies
Citations of potentially relevant studies were entered on the reference management system
Endnote. The abstracts of potentially relevant studies were screened by one methodologist to
form a list of potentially eligible studies. Studies in the list were independently matched against
the pre-specified eligibility criteria by two methodologists.
B.3v
Inclusion criteria
Consistent with the principles of ADAPTE, only systematic review and randomised controlled trial
(RCT) evidence was considered for inclusion to answer intervention/therapy questions. Systematic
reviews were included if they had one or more clearly formulated questions, and used systematic
and explicit methods to identify, select and critically appraise relevant research, and to collect and
analyse data from the studies included in the review. RCTs were included if they had two or more
groups formed by randomisation with concealed allocation of the randomisation.
The evidence tables from the NICE guidelines were reproduced into standardised data extraction
tables (modelled on the NICE template) and then regrouped according to the surgical procedure
being considered. Where systematic reviews for a particular intervention were included in the
NICE guidelines and the different surgical indications were grouped together it was not possible
to include the data extraction table from NICE directly unless the results could be separated by
surgical indication. Instead, the original systematic review was used a source document and the
individual data from the included randomised trials was tabulated into the standardised data
extraction tables. In cases where the NICE guidelines included a systematic review of only one
surgical intervention then the systematic review itself was considered as the included study.
For each new included study, descriptive details, results and critical appraisal of the study were
entered into the standardised data extraction table. Data extraction was checked by a second
methodologist. The level of evidence for each study has been designated according to the NHMRC
levels of evidence (see table on next page).22 The methods used to conduct the critical appraisal
and summarise the evidence comply with NHMRC requirements17-19 and are described in Appendix
B.3vi. The evidence tables describing the identified studies are provided in Appendix D.
91
A pseudorandomised controlled trial
(i.e. alternate allocation or some
other method)
A comparative study with
concurrent controls:
•non-randomised, experimental trial
•cohort study
•case-control study
•interrupted time series with a
control group
A comparative study without
•historical control study
•two or more single arm study
•interrupted time series without a
parallel control group
Case series with either post-test or
pre-test/post-test outcomes
III-2
III-3
IV
A randomised controlled trial
II
III-1
A systematic review of level II studies
Intervention
I
Level
Analysis of prognostic
factors amongst
persons in a single
arm of a randomised
controlled trial
A retrospective
cohort study
A comparison with reference standard
that does not meet the criteria
required for level II and III-1 evidence
Diagnostic case-control study
Study of diagnostic yield
(no reference standard)
Case series, or
cohort study of
persons at different
stages of disease
All or none
All or none
A study of test accuracy with: an
independent, blinded comparison
with a valid reference standard, among
non-consecutive persons with a
defined clinical presentation6
A cross-sectional
study or case series
A case-control study
A retrospective
cohort study
A prospective
cohort study
A study of test accuracy with: an
independent, blinded comparison
with a valid reference standard,
among consecutive persons with a
defined clinical presentation6
A prospective
cohort study
Aetiology
A systematic review
of level II studies
Prognosis
A systematic review
of level II studies
Diagnostic accuracy
Case series
A comparative study without
•historical control study
•two or more single arm study
A comparative study with
•non-randomised, experimental trial
•cohort study
•case-control study
A pseudorandomised controlled trial
(i.e. alternate allocation or some
other method)
A randomised controlled trial
Screening Intervention
NHMRC Evidence hierarchy: designations of ‘levels of evidence’ according to type of research question22
B.3vi Critically appraising included studies
For studies adapted directly from the NICE guidelines evidence tables, the critical appraisal quality
rating was accepted directly. In all cases, the included RCTs taken from the NICE guidelines were
rated with a low risk of bias. New studies and those obtained from other source systematic reviews
were appraised according to the potential risk of bias associated with the study design according to
the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0. Studies considered
as having a low risk of bias allocated participants using an accepted method of randomisation with
adequately concealed allocation and minimal losses to follow-up. It was noted that most RCTs
using rates of deep vein thrombosis as an outcome must rely on diagnostic tests of DVT which
have varying acceptability. Venography is often used to assess DVT, and is an invasive test and
typically up to one quarter of participants in a research study will not have a DVT result confirmed
by this method leading to relatively high “losses” to follow-up. However, as these are distributed
equally across both groups in the study, it was not expected that this would introduce in an
unacceptable level of bias to the included studies.
B.3vii Summarise and where appropriate statistically pool the relevant data
As all the evidence included in this Guideline came from randomised trials which were generally
considered to be at low risk of bias it was appropriate to pool data whenever there was more
than one study considering the same intervention for the same indication or patient population.
Meta-analysis was undertaken using RevMan version 5. Relative risks and 95% confidence intervals
were calculated used a fixed effects method unless heterogeneity was high (I2≥50%) in which
case a random effects analysis was used. Forest plots were provided to assist the Committee in
discussion of the evidence. In order to examine the possibility that different diagnostic methods
for detecting DVT would influence the outcomes, pre-planned subgroup analyses were undertaken
by diagnostic method (blinded and unblinded) for all DVT related outcomes. Posthoc subgroup
analyses were also undertaken to examine the impact of background method of prophylaxis on
the main effects.
B.3viii Assess the body of evidence and formulate recommendations
The body of evidence was assessed by the entire Committee with regard for the volume of
evidence, its consistency, the clinical impact, generalisability and applicability. These aspects
were graded according to the NHMRC grading criteria.22 Following the grading of the evidence,
the committee formulated a recommendation that reflected the summarised body of evidence.
The overall recommendations were graded as follows:
Grade of recommendation
Description
A
Body of evidence can be trusted to guide practice
B
Body of evidence can be trusted to guide practice in most situations
C
Body of evidence provides some support for recommendation(s) but care should be taken
in its application
D
Body of evidence is weak and recommendation must be applied with caution
NA
Not applicable – unable to grade body of evidence
GPP
Good practice point - consensus-based recommendations
The process of formulating recommendations occurred over eight full-day meetings that took place
from July to December 2008.
93
Appendix C: Clinical questions
Below is a list of the clinical questions which were addressed within this Guideline. These were
generated at the first VTE Prevention Guideline Adaptation Committee meeting on 12 June 2008.
Categories marked with * are those where the question was posed but no evidence of suitable
quality existed.
1. What is the risk of developing VTE in the following surgical and medical patients
(listed in Table 1 and 2 below)?
2. How should each group be managed with regard to VTE prophylaxis? In addition to adequate
hydration and early ambulation as standard, what pharmacological and/or mechanical
prophylaxis is the appropriate management (with consideration of the type of indication,
timing and dosing regimens and alternatives)?
Table 1: Surgical patients
Surgical type
Procedure
Major and minor orthopaedic including:
Total and partial knee replacement
Knee arthroscopy and arthroscopic knee surgery (minor and major)
Foot fracture
Pelvic fracture
Isolated below knee injuries
Non-operable orthopaedic injury
General
Cancer
Gynaecological
Cardiothoracic
Urological
Neurosurgery
Vascular
Head and neck
Plastic and reconstructive*
Trauma
Elective spine
Bariatric*
Intensive care
Laparoscopic*
Gynaecological including:
Obstetrics
Hysterectomy
Any surgical procedure >45 mins
Table 2: Medical patients
Type of medical patient
Acutely ill
Cancer including:
patients receiving radiotherapy
patients treated with anti-angiogenic agents
patients with a central venous catheter
patients with particular cancer types at higher risk of developing VTE including:
head and neck, thoracic, solid tumours, breast cancer, myeloma
patients receiving chemotherapy
Burns*
Stroke
Obstetrics
Cardiothoracic including:
patients with heart failure taking anti-platelet/anticoagulants
(these patients receive arterial thromboprophylaxis not venous)
patients with decompensated cardiac failure
haematological patients with decreased platelet count
Renal* including:
patients with renal failure/insufficiency*
Active Infection (i.e. cellulitis, pneumonia)
Respiratory conditions
Spinal cord injury
Intensive care
Palliative care*
Patient characteristics
Do the following patient characteristics increase the risk of developing VTE? If so, how should
surgical and medical patients with the following patient characteristics be managed with regard
to VTE prophylaxis?
•Age
–– is age an independent risk factor for patients with medical conditions (in particular in patients
with active cancer or respiratory problems)
–– is this different between surgical and medical patients?
•Obesity (including severely obese patients)
•Previous VTE
• Increased risk of bleeding with medical prophylaxis (including patients with low platelet count;
coagulation deficiencies; patients on particular complementary therapies; patients with liver disease)
•Any active inflammatory condition
•Patients with inherited or acquired thrombophilia
•Patients with a family history of VTE
•Pregnant women (including women admitted to hospital during pregnancy; pregnant women
undergoing caesarean; pregnant women delivering via vaginal delivery; pregnant women with
pre-eclampsia; pregnant women receiving an epidural)
•Patients with chronic venous disease
•Patients with varicose veins
95
•Patients currently taking oral contraception (OC) or hormone replacement therapy (HRT) – when
should OC or HRT be stopped?
•Patients taking low dose aspirin
•Immobilisation including recent prolonged travel prior to surgery
Options for thromboprophylaxis
Consider and review evidence for all of the following options for thromboprophylaxis for each of
the surgical or medical categories in Tables 1 and 2.
Dosing regimens
Pharmacological
•Unfractionated heparin (UFH) (effects and regimens)
•Low molecular weight heparin (LMWH) (effects, regimens)
•Fondaparinux (effects, regimens)
•Aspirin (effects, regimens)
•Warfarin (effects, regimens)
•Oral thrombin (effects, regimens)
•Factor Xa inhibitors (effects, regimens)
Mechanical
•Graduated compression stockings (GCS) (effects, regimens)
•What are the comparative effects of full length GCS compared with knee length GCS?
•Intermittent pneumatic compression (IPC) (effects, regimens)
•What are the comparative effects of GCS and IPC?
•What are the combined effects of GCS and IPC?
•Foot impulse technology (effects, regimens)
Anaesthesia
•What is the risk of VTE for patients receiving spinal/epidural vs. general anaesthesia?
•What are the risks of complications from anaesthesia such as epidural haematoma in patients
receiving VTE pharmacoprophylaxis?
•What is the optimal timing of prophylaxis?
•What should be the timing of epidural for pregnant women on thromboprophylaxis?
•Can delaying systemic pharmacological anticoagulants until after the insertion of the epidural
catheter or ensuring that pharmacological anticoagulants agents are not administered within six
hours prior to the insertion or six hours following withdrawal of an epidural catheter reduce the
rate of complications?
Other
•What is the acceptability of different treatments to patients?
•Does patient understanding of VTE risk and prophylaxis affect adherence?
•How do patients understand the risks associated with prophylaxis?
•How do patients balance the risk of bleeding against the risk of clotting?
•What are the costs or cost-effectiveness of VTE prophylaxis?
•What helps or hinders patient adherence /compliance?
•What are the effects of implementation systems in achieving compliance with VTE
prophylaxis guidelines?
Appendix D: Evidence tables
Full evidence tables available at http://www.nhmrc.gov.au/nics/programs/vtp/consultation.htm
97
A level I or several level II studies with low risk of bias
One or two Level II studies with low risk of bias or SR/multiple level III studies with low risk of bias
Level III studies with low risk of bias or level I or II studies with moderate risk of bias
Level IV studies or level I to III studies with high risk of bias
A
B
C
D
Most studies consistent and inconsistency can be explained
Some inconsistency, reflecting genuine uncertainty around question
Evidence is inconsistent
Not applicable (one study only)
B
C
D
NA
Very large
Moderate
Slight
Restricted
A
B
C
D
options, resource implications, and the balance of risk versus benefit. If the intervention is shown to have an effect, does it have the potential to reduce burden of disease?
3. Clinical impact – Comment here on the potential clinical impact that the intervention might have. Factors to consider are: size of patient population, magnitude of effect, relative benefit over other management
All studies consistent
A
overall direction of the evidence. If only one study was available, rank this component as ‘not applicable’.
2. Consistency – Comment here on the degree of consistency demonstrated by the available evidence between the studies. Where there are conflicting results, indicate how the group formed a judgment as to the
1. Evidence base – Number of studies, level of evidence and risk of bias in the included studies
• What is the risk of developing VTE in these patients?
• How should these patients be managed with regard to VTE prophylaxis? In addition to adequate hydration and early ambulation as standard, what pharmacological and/or mechanical prophylaxis is the
appropriate management (with consideration of the type of indication, timing and dosing regimens and alternatives)?
• Are there any contraindications to prophylaxis in these patients?
Key question(s):
(If rating is not completely clear, use the space next to each criteria to note how the group came to a judgment.)
Appendix E: NHMRC Evidence Statement Form
Evidence directly generalisable to target population with some caveats
Evidence not directly generalisable to the target population but could be sensibly applied
Evidence not directly generalisable to target population and hard to judge whether it is sensible to apply
C
D
Evidence directly generalisable to target population
B
A
Evidence applicable to Australian healthcare context with few caveats
Evidence probably applicable to Australian healthcare context with some caveats
Evidence not applicable to Australian healthcare context
B
C
D
Rating
Indicate any dissenting opinions
4. Applicability
3. Clinical impact
2. Consistency
1. Evidence base
Component
Description
Please summarise the development group’s synthesis of the evidence relating to the key question, taking all the above factors into account.
EVIDENCE STATEMENT MATRIX
Other factors (Indicate here any other factors that you took into account when assessing the evidence base (for example, issues that might cause the group to downgrade or upgrade the recommendation.)
Evidence directly applicable to Australian healthcare context
A
specialised equipment, tests and other resources) and cultural factors (eg attitudes to health issues, including those that may affect compliance with the recommendations).
5. Applicability – factors that may reduce the direct application of study findings to the Australian or more local settings include organisational factors (eg availability of trained staff, clinic time, accessibility of
4. Generalisability
NHMRC Evidence Statement Form (continued)
99
Grade of
recommendation
Is the guideline development group aware of any barriers to the implementation of this recommendation?
Will the implementation of this recommendation require changes in the way care is currently organised?
Is there any resource implications associated with implementing this recommendation?
Will this recommendation result in changes in usual care?
NO
YES
NO
YES
NO
YES
NO
YES
Please indicate yes or no to the following questions. Where the answer is yes please provide explanatory information about this. This information will be used to develop the implementation plan for the guidelines.
IMPLEMENTATION OF RECOMMENDATION
ANY UNRESOLVED ISSUES?
What recommendation(s) does the guideline development group draw from this evidence? Use action statements where possible.
RECOMMENDATION
NHMRC Evidence Statement Form (continued)
Appendix F: Abbreviations and glossary of terms
Abbreviations
ACCP
The American College of Chest Physicians
ADAPTE
AGREE
ANZCA
BMI
CECT
CI
COPD
CR
DVT
FID
FIT
FUT
GCS
GP
HIT
HTA
INR
IPC
IV
LMWH
MOGA
NA
NHMRC
NICE
NICS
NNTB
NNTH
NR
OAC
OR
PICO
The ADAPTE Guideline Adaptation Framework
Appraisal of Guidelines Research & Evaluation
The Australian and New Zealand College of Anaesthetists
Body mass index
Continuous enhanced circulation therapy
Confidence interval
Chronic obstructive pulmonary disease
Cochrane review
Deep vein thrombosis
Foot impulse device
Foot impulse technology
I-Fibrinogen uptake test125
Graduated compression stockings
General practitioner
Heparin-induced thrombocytopaenia
Health technology assessment report
International normalised ratio
Intermittent pneumatic compression
Intravenous
Low molecular weight heparin
The Medical Oncology Group of Australia
Not applicable
National Health and Medical Research Council
National Institute for Health and Clinical Excellence, United Kingdom
National Institute of Clinical Studies
Number needed to treat to benefit
Number needed to treat to harm
Not reported
Oral anticoagulant
Odds ratio
Guidance on the key components of a well formulated clinical question which incorporates Patients,
Interventions, Comparisons and Outcomes
Post-thrombotic limb syndrome
The Royal Australasian College of Surgeons
The Royal Australasian College of Physicians
The Royal Australian and New Zealand College of Obstetrics and Gynaecology
Randomised controlled trial
The Royal College of Nursing, Australia
Risk ratio
Subcutaneous
The Society of Hospital Pharmacists Australia
Systematic review
Therapeutic Goods Administration
Unfractionated heparin
Ultrasound
Venous foot pump
Venous thromboembolism
Venous thrombosis
PTS
RACS
RACP
RANZCOG
RCT
RCNA
RR
SC
SHPA
SR
TGA
UFH
US
VFP
VTE
VT
101
Glossary of terms
Most of these have been taken from the NICE VTE prevention guidelines, 2007 and the Cochrane
Resources Glossary- http://www.cochrane.org/resources/glossary.htm).
Absolute risk reduction
(risk difference)
The difference in the risk of an event between two groups (one subtracted from the other) in a
comparative study.
Abstract
Summary of a study, which may be published alone or as an introduction to a full scientific paper.
Absolute risk reduction
The difference in size of risk between two groups. For example, if one group has a 15 percent
risk of contracting a particular disease, and the other has a 10 percent risk of getting the disease,
the absolute risk reduction is five percentage points. (Also called risk difference or absolute
risk difference).
Acute embolic stroke
Sudden onset of focal neurological deficit of vascular causation with CT or MRI scan confirmation
of an ischaemic aetiology associated with a likely embolic source and typically in a large vessel
distribution.
Acute ischemic stroke
Sudden onset of focal neurological deficit of vascular causation with CT or MRI scan confirmation
of an ischaemic aetiology.
Adverse event
An adverse outcome that occurs during or after the use of a drug or other intervention but is not
necessarily caused by it.
Algorithm
(in guidelines)
A flow chart of the clinical decision pathway described in the guideline, where decision points are
represented with boxes, linked with arrows.
Allocation concealment
The process used to prevent advance knowledge of group assignment in a RCT. The allocation
process should be impervious to any influence by the individual making the allocation, by being
administered by someone who is not responsible for recruiting participants.
Anticoagulant
Any agent used to prevent the formation of blood clots. These include oral agents, such as
warfarin, and others which are injected into a vein or under the skin, such as heparin.
Applicability
The degree to which the results of an observation, study or review are likely to hold true in a
particular clinical practice setting.
(AGREE) – Appraisal
of Guidelines, Research
and Evaluation
An international collaboration of researchers and policy makers whose aim is to improve the quality
and effectiveness of clinical practice guidelines (http://www.agreecollaboration.org). The AGREE
instrument, developed by the group, is designed to assess the quality of clinical guidelines.
Arm (of a clinical study)
Group of individuals within a study who are allocated to one particular intervention, for example
the placebo arm.
Baseline
The initial set of measurements at the beginning of a study (after run-in period where applicable),
with which subsequent results are compared.
Bias
Systematic (as opposed to random) – deviation of the results of a study from the ‘true’ results
that is caused by the way the study is designed or conducted.
Blinding
In a controlled trial – The process of preventing those involved in a trial from knowing to which
comparison group a particular participant belongs. The risk of bias is minimised when as few
people as possible know who is receiving the experimental intervention and who the control
intervention. Participants, caregivers, outcome assessors, and analysts are all candidates for
being blinded. Blinding of certain groups is not always possible, for example surgeons in surgical
trials. The terms single blind, double blind and triple blind are in common use, but are not used
consistently and so are ambiguous unless the specific people who are blinded are listed. Blinding is also called masking.
Body mass index
A statistical measurement which compares a person’s weight and height (body weight in
kilograms/height in metres squared).
Carer (caregiver)
Someone other than a health professional who is involved in caring for a person with a
medical condition.
Case-control study
A study that compares people with a specific disease or outcome of interest (cases) to people
from the same population without that disease or outcome (controls), and which seeks to find
associations between the outcome and prior exposure to particular risk factors. This design is
particularly useful where the outcome is rare and past exposure can be reliably measured.
Case-control studies are usually retrospective, but not always.
Case series
Report of a number of cases of a given disease, usually covering the course of the disease and the
response to treatment. There is no comparison (control) group of patients.
Case study
A study reporting observations on a single individual. (Also called anecdote, case history, or single
case report.)
Clinical audit
A quality improvement process that seeks to improve patient care and outcomes through
systematic review of care against explicit criteria and the implementation of change.
Clinical efficacy
The extent to which an intervention is active when studied under controlled research conditions.
Clinical effectiveness
The extent to which an intervention produces an overall health benefit in routine clinical practice.
Clinical impact
The effect that an intervention is likely to have on the treatment or treatment outcomes of the
target population.
Clinical question
In guideline development, this term refers to the questions about treatment and care that are
formulated to guide the development of evidence-based recommendations.
Clinical trial
An experiment to compare the effects of two or more healthcare interventions. Clinical trial is an
umbrella term for a variety of designs of healthcare trials, including uncontrolled trials, controlled
trials, and randomised controlled trials. (Also called intervention study)
Clinician
A healthcare professional providing direct patient care, for example doctor, nurse or physiotherapist.
Cluster
A closely grouped series of events or cases of a disease or other related health phenomenon with
well-defined distribution patterns, in relation to time or place or both. Alternatively, a grouped unit
for randomisation.
Cochrane Library
A regularly updated electronic collection of evidence-based medicine databases, including the
Cochrane Database of Systematic Reviews.
Cochrane Review
A systematic review of the evidence from randomised controlled trials relating to a particular
health problem or healthcare intervention, produced by the Cochrane Collaboration.
Available electronically as part of the Cochrane Library.
Cohort study
A retrospective or prospective follow-up study. Groups of individuals to be followed up are defined
on the basis of presence or absence of exposure to a suspected risk factor or intervention. A cohort
study compares groups with different levels of exposure or different exposures.
Co-morbidity
Co-existence of more than one disease or an additional disease (other than that being studied
or treated) in an individual.
Compliance
The extent to which a person adheres to the health advice agreed with healthcare professionals.
May also be referred to as ‘adherence’ or ‘concordance’.
Confidence interval
A range of values for an unknown population parameter with a stated ‘confidence’ (conventionally
95%) that it contains the true value. The interval is calculated from sample data, and generally
straddles the sample estimate. The ‘confidence’ value means that if the method used to calculate the
interval is repeated many times, then that proportion of intervals will actually contain the true value.
Confounder
A factor that is associated with both an intervention (and exposure) and the outcome of interest.
For example, if people in the experimental group of a controlled trial are younger than those in
the control group, it will be difficult to decide whether a lower risk of death in one group is due
to the intervention or the difference in ages. Age is then said to be a confounder, or a confounding
variable. Randomisation is used to minimise imbalances in confounding variables between
experimental and control groups. Confounding is a major concern in non-randomised studies.
(See also adjusted analyses.)
103
Consensus methods
Techniques that aim to reach an agreement on a particular issue. Formal consensus methods
include Delphi and nominal group techniques, and consensus development conferences. In the
development of clinical guidelines, consensus methods may be used where there is a lack of
strong research evidence on a particular topic. Expert consensus methods will aim to reach
agreement between experts in a particular field.
Continuous enhanced
circulation therapy
Pneumatic compression devices that create pressure and apply it to the patient’s limbs.
Battery-operated compression devices that can be used continuously.
Control group
A group of patients recruited into a study that receives no treatment, a treatment of known effect,
or a placebo (dummy treatment) – in order to provide a comparison for a group receiving an
experimental treatment, such as a new drug.
Controlled clinical trial
A study testing a specific drug or other treatment involving two (or more) groups of patients with
the same disease. One (the experimental group) receives the treatment that is being tested, and
the other (the comparison or control group) receives an alternative treatment, a placebo (dummy
treatment) or no treatment. The two groups are followed up to compare differences in outcomes
to see how effective the experimental treatment was. A controlled clinical trial where patients are
randomly allocated to treatment and comparison groups is called a randomised controlled trial.
Cost benefit analysis
A type of economic evaluation where both costs and benefits of healthcare treatment are
measured in the same monetary units. If benefits exceed costs, the evaluation would recommend
providing the treatment.
Cost-effectiveness
analysis
An economic study design in which consequences of different interventions are measured using
a single outcome, usually in ‘natural’ units (For example, life-years gained, deaths avoided, heart
attacks avoided, cases detected). Alternative interventions are then compared in terms of cost
per unit of effectiveness.
Deep vein thrombosis
A blood clot that occurs in the “deep veins” in the legs, thighs or pelvis. Asymptomatic deep
vein thrombosis is defined as painless DVT detected only by screening with fibrinogen scanning,
ultrasound, or ascending venography and is often confined to the distal veins and, when it involves
the proximal veins, the thrombi usually are smaller than in symptomatic patients with proximal
thrombosis. Symptomatic deep vein thrombosis results from occlusion of a major leg vein and
results in leg pain or swelling. It requires specific investigation and treatment which in hospitalised
patients may delay discharge, or require readmission to hospital.
Distal
Refers to a part of the body that is farther away from the centre of the body than another part.
Dosage
The prescribed amount of a drug to be taken, including the size and timing of the doses.
Double blind study
A study in which neither the subject (patient) nor the observer (investigator/clinician) is aware of
which treatment nor intervention the subject is receiving. The purpose of blinding is to protect
against bias.
Drop-out
The loss of participants during the course of a study. (Also called loss to follow up). The loss of
participants during the study can also be referred to as attrition.
Effect (as in effect
measure, treatment
effect, estimate of
effect, effect size)
The observed association between interventions and outcomes or a statistic to summarise the
strength of the observed association.
Elective
Name for clinical procedures that are planned and booked in advance as opposed to emergency
procedures which may take precedence.
Electrical stimulation
Designed to caused muscle contractions and thereby increase venous blood flow velocity out of
the leg to reduce the incidence of post-surgical venous thrombosis.
Emboli
Material propagated through the circulatory system.
Epidemiological study
The study of a disease or health issue within a population, defining its incidence and/or prevalence
and examining the roles of various possible confounding factors (for example: infection, diet)
and interventions.
Evidence table
A table summarising the results of a collection of studies which, taken together, represent the
evidence supporting a particular recommendation or series of recommendations in a guideline.
Exclusion criteria
(for a literature review)
Explicit criteria used to decide which studies should be excluded from consideration as potential
sources of evidence.
Exclusion criteria
(for a clinical study)
Criteria that define who is not eligible to participate in a clinical study.
External validity
The extent to which results provide a correct basis for generalisations to other circumstances.
For instance, a meta-analysis of trials of elderly patients may not be generalisable to children.
(Also called generalisability or applicability.)
Extrapolation
In data analysis, predicting the value of a parameter outside the range of observed values.
125I-Fibrinogen
uptake test
A fibrinogen uptake test is a test that was formerly used to detect deep vein thrombosis.
Radioactive labelled fibrinogen is given which is incorporated in the thrombus. The thrombus
can then be detected by scintigraphy.
Follow-up
The observation over a period of time of study/trial participants to measure outcomes
under investigation.
Foot impulse device
The foot impulse device is designed to stimulate the leg veins (venous pump) artificially by
compressing the venous plexus and mimicking normal walking and reducing stasis in immobilised
patients. Other names for this method of mechanical VTE prophylaxis include: foot impulse
technology (FIT) or venous foot pump (VFP).
Forest plot
A graphical representation of the individual results of each study included in a meta-analysis
together with the combined meta-analysis result. The plot also allows readers to see the
heterogeneity among the results of the studies. The results of individual studies are shown as
squares centred on each study’s point estimate. A horizontal line runs through each square
to show each study’s confidence interval – usually, but not always, a 95% confidence interval.
The overall estimate from the meta-analysis and its confidence interval are shown at the bottom,
represented as a diamond. The centre of the diamond represents the pooled point estimate,
and its horizontal tips represent the confidence interval.
Graduated
compression stockings
Mechanical method of prophylaxis. Stockings manufactured to provide compression around the legs
at gradually increasing pressures. There are different standards for graduated compression stockings
so it is suggested that mmHg (mm Mercury) be considered. Also known as anti-embolism stockings.
Haemorrhagic stroke
Sudden onset of focal neurological deficit of vascular causation with CT or MRI scan confirming
a haemorrhagic aetiology.
Harms
Adverse effects.
Heparin-induced
thrombocytopaenia
Low blood platelet count resulting from the administration of heparin (or heparin-like agents).
Despite having a low platelet count, patients with this condition are at high risk of their
blood clotting.
Heterogeneity
Or lack of homogeneity. Used in a general sense to describe the variation in, or diversity of,
participants, interventions, and measurement of outcomes across a set of studies, or the variation in
internal validity of those studies. It can be used specifically, as statistical heterogeneity, to describe the
degree of variation in the effect estimates from a set of studies. Also used to indicate the presence
of variability among studies beyond the amount expected due solely to the play of chance.
The term is used in meta-analyses and systematic reviews when the results or estimates of effects
of treatment from separate studies seem to be very different – in terms of the size of treatment
effects or even to the extent that some indicate beneficial and others suggest adverse treatment
effects. Such results may occur as a result of differences between studies in terms of the patient
populations, outcome measures, definition of variables or duration of follow-up.
Homogeneity
This means that the results of studies included in a systematic review or meta-analysis are similar
and there is no evidence of heterogeneity. Results are usually regarded as homogeneous when
differences between studies could reasonably be expected to occur by chance.
Homogeneous
Used in a general sense to mean that the participants, interventions, and measurement of
outcomes are similar across a set of studies. Can also be used specifically to describe the effect
estimates from a set of studies where they do not vary more than would be expected by chance.
105
Impedance
plethysmography
A non-invasive test that uses electrical monitoring in the form of resistance (impedance) changes to
measure blood flow in veins of the leg. Information from this test assists in the detection of DVT.
Incidence
The number of new occurrences of something in a population over a particular period of time,
e.g. the number of cases of a disease in a country over one year. Inclusion criteria
(for a literature review)
Explicit criteria used to decide which studies should be considered as potential sources of evidence.
International
normalised ratio
A laboratory test used to measure the level of coagulant activity of vitamin-K dependent clotting
factors in a plasma sample compared to a normal and standardised control. It is used to monitor
the anticoagulant activity of warfarin and is also sensitive to changes in liver function which
manufactures these clotting factors.
Intermittent pneumatic
compression
A mechanical method of VTE prophylaxis that comprises the use of inflatable garments wrapped
around the legs, inflated by a pneumatic pump. The pump provides intermittent cycles of compressed
air which alternatively inflates and deflates the chamber garments, enhancing venous return.
Internal validity
The degree to which the results of a study are likely to approximate the ‘truth’ for the participants
recruited in a study (that is, are the results free of bias?)? It refers to the integrity of the design and
specifically the extent to which the design and conduct of a study are likely to have prevented bias.
Variation in quality can explain variation in the results of studies included in a systematic review.
More rigorously designed (better quality) trials are more likely to yield results that are closer to the
truth. (Also called methodological quality but better thought of as relating to bias prevention).
Intervention
Any action intended to benefit the patient, for example, drug treatment, surgical procedure,
psychological therapy.
Intraoperative
The period of time during a surgical procedure.
Length of stay
The total number of days a patient stays in hospital.
Low molecular
weight heparin
A low molecular weight fraction of heparin isolated specifically for its ability to bind to clotting
factor Xa. Requires subcutaneous administration.
Meta-analysis
A statistical technique for combining (pooling) the results of a number of studies that address the
same question and report on the same outcomes to produce a summary result. The aim is to
derive more precise and clear information from a large data pool. It is generally more reliably likely
to confirm or refute a hypothesis than the individual trials.
Multicentre trial
A trial conducted at several geographical sites. Trials are sometimes conducted among several
collaborating institutions, rather than at a single institution – particularly when very large numbers
of participants are needed.
Narrative summary
Summary of findings given as a written description.
Number needed to
treat to benefit
An estimate of how many people need to receive a treatment before one person would experience
a beneficial outcome. For example, if you need to give a stroke prevention drug to 20 people before
one stroke is prevented, then the number needed to treat to benefit for that stroke prevention
drug is 20. The NNTB is estimated as the reciprocal of the absolute risk difference. Number needed to
treat to harm
A number needed to treat to benefit associated with a harmful effect. It is an estimate of how
many people need to receive a treatment before one more person would experience a harmful
outcome or one fewer person would experience a beneficial outcome.
Observational study
A study in which the investigators do not seek to intervene, and simply observe the course of
events. Changes or differences in one characteristic (e.g. whether or not people received the
intervention of interest) are studied in relation to changes or differences in other characteristic(s)
(e.g. whether or not they died), without action by the investigator. There is a greater risk of
selection bias than in experimental studies.
P values
The probability that an observed difference could have occurred by chance, assuming that there
is in fact no underlying difference between the means of the observations. If the probability
is less than one in 20, the P value is less than 0.05; a result with a P value of less than 0.05 is
conventionally considered to be ‘statistically significant’.
Peer review
A process where research is scrutinised by experts that have not been involved in the design
or execution of the studies. An article submitted for publication in a peer-reviewed journal is
reviewed by other experts in the area.
Perioperative
The period from admission through surgery until discharge, encompassing preoperative and
postoperative periods.
Pulmonary embolism
(plural = pulmonary
emboli)
A blood clot that breaks off from the deep veins and travels around the circulation to block the
pulmonary arteries (arteries in the lung). Most deaths arising from deep vein thrombosis are
caused by pulmonary emboli.
Placebo
An inactive substance or preparation used as a control in an experiment or test to determine the
effectiveness of a medicinal drug.
Placebo effect
A beneficial (or adverse) effect produced by a placebo and not due to any property of the
placebo itself.
Post-thrombotic
limb syndrome
Chronic pain, swelling, and occasional ulceration of the skin of the leg that occur as a consequence
of previous venous thrombosis.
Postoperative
Pertaining to the period after patients leave the operating theatre, following surgery.
Preoperative
Pertaining to the period before surgery commences.
Primary research
Study generating original data rather than analysing data from existing studies (which is called
secondary research).
Proximal
Refers to a part of the body that is closer to the centre of the body than another part.
Proximal DVT
A DVT occurring in deep knee or thigh veins, known as proximal DVT. A proximal DVT is likely to
involve the same amount of vein whether it is symptomatic or asymptomatic i.e. an asymptomatic
proximal DVT is not necessarily smaller than a symptomatic proximal DVT.
Pulmonary embolism
A blood clot that breaks off from the deep veins and travels round the circulation to block the
pulmonary arteries (arteries in the lung). Most deaths arising from DVT are caused by PE.
Prophylaxis
A measure taken for the prevention of a disease.
Prospective study
A study in which people are entered into the research and then followed up over a period
of time with future events recorded as they happen. This contrasts with studies that are
retrospective.
Qualitative research
Research concerned with phenomena that are described rather than measured numerically.
Quantitative research
Research that generates numerical data or data that can be converted into numbers, for example
clinical trials or case controlled studies.
Randomisation
Allocation of participants in a research study to two or more alternative groups using a chance
procedure, such as computer-generated random numbers. This approach is used in an attempt to
ensure there is an even distribution of participants with different characteristics between groups
and thus reduce sources of bias.
Randomised
controlled trial
A comparative study in which participants are randomly allocated to intervention and control
groups and followed up to examine differences in outcomes between the groups.
Relative risk
The number of times more likely or less likely an event is to happen in one group compared
with another (calculated as the risk of the event in group A/the risk of the event in group B).
Also called risk ratio.
Resource implication
The likely impact in terms of cost, workforce or other health system resources.
Retrospective study
A retrospective study deals with the present/ past and does not involve studying future events.
This contrasts with studies that are prospective.
Risk difference
The difference in size of risk between two groups. For example, if one group has a 15 percent risk
of contracting a particular disease, and the other has a 10 percent risk of getting the disease, the
risk difference is five percentage points.
107
Risk ratio
The ratio of risks in two groups. In intervention studies, it is the ratio of the risk in the intervention
group to the risk in the control group. A risk ratio of one indicates no difference between
comparison groups. For undesirable outcomes, a risk ratio that is less than one indicates that the
intervention was effective in reducing the risk of that outcome. (Also called relative risk, RR.)
Selection bias
1. Systematic differences between comparison groups in prognosis or responsiveness to
treatment. Random allocation with adequate concealment of allocation protects against
selection bias. Other means of selecting who receives the intervention are more prone to
bias because decisions may be related to prognosis or responsiveness to treatment.
2. A systematic error in reviews due to how studies are selected for inclusion. Reporting bias
is an example of this.
3. A systematic difference in characteristics between those who are selected for study and those
who are not. This affects external validity but not internal validity.
Selection criteria
Explicit standards used by guideline development groups to decide which studies should be
included and excluded from consideration as potential sources of evidence.
Stakeholder
Those with an interest in the use of a technology under appraisal or a guideline under
development. Stakeholders include manufacturers, sponsors, healthcare professionals, and patient
and carer groups.
Statistical power
The ability to demonstrate an association when one exists. Power is related to sample size; the
larger the sample size, the greater the power and the lower the risk that a possible association
could be missed.
Systematic review
A review of a clearly formulated question that uses systematic and explicit methods to identify,
select, and critically appraise relevant research, and to collect and analyse data from the studies
that are included in the review. Statistical methods (meta-analysis) may or may not be used to
analyse and summarise the results of the included studies.
Thrombophilia
The genetic or acquired pro-thrombotic states that increase the tendency to venous (or arterial)
thromboembolism. It is a condition which leads to a tendency for a person’s blood to clot
inappropriately.
Thromboprophylaxis
A measure taken to reduce the risk of thrombosis.
Treatment allocation
Assigning a participant to a particular arm of the trial.
Unfractionated heparin
Naturally-occurring polysaccharide anticoagulant isolated for pharmacological use from pig
intestine or bovine lung. Usually given as subcutaneous injection as prophylaxis or by continuous
infusion as therapy for a thrombosis.
Venous
thromboembolism
The blocking of a blood vessel by a blood clot dislodged from its site of origin. It includes both
deep vein thrombosis and pulmonary embolism.
Venous thrombosis
A condition in which a blood clot (thrombus) forms in a vein.
Appendix G: Acknowledgements
In addition to the VTE Prevention Guideline Adaptation Committee, the following individuals have
contributed significantly in the development of this Guideline using the ADAPTE methodology:
Sonja Hood
Acting Director, Research Implementation Program, National Institute of Clinical Studies
Dr Heather Buchan
Advisor, National Health and Medical Research Council
Catherine Marshall
Independent guidelines advisor
Dr Jako Burgers
Guideline Program Director at the Dutch Institute for Healthcare Improvement CBO.
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CliniCal praCtiCe guideline for the prevention of venous thromboembolism

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